CN101005838A

CN101005838A - Cannabinoid receptor ligands

Info

Publication number: CN101005838A
Application number: CNA2005800284680A
Authority: CN
Inventors: B·B·尚卡; E·吉尔伯特; R·K·里兹维; C·黄; J·A·科兹洛夫斯基; S·麦坎比; 施能扬
Original assignee: Schering Corp
Current assignee: Merck Sharp and Dohme Corp
Priority date: 2004-06-22
Filing date: 2005-06-21
Publication date: 2007-07-25
Also published as: HK1097189A1; US7750158B2; US20060100228A1; CA2571058A1; WO2006002133A1; MX2007000015A; EP1768667A1; EP1768667B1; DE602005016929D1; ATE444066T1; ES2332416T3; JP2008503585A

Abstract

Compounds of Formula (I) and/or pharmaceutically acceptable salts, solvates or prodrugs thereof, or pharmaceutical compositions containing such compounds exhibit anti-inflammatory and immunomodulatory activity, and can be effective as CB2 acceptor and matcher to cure cancer and inflammation, immunomodulatory or respiration system disease.

Description

Cannabinoid receptor ligand

The U.S. Provisional Application No.60/581 that the application submitted on June 22nd, 1,837 rights and interests.

Background

The present invention relates to be used as the chemical compound of cannabinoid receptor ligand, more particularly, relate to and cannabinoid (CB ₂) chemical compound of receptors bind.Chemical compound of the present invention can show antiinflammatory and immunoregulatory activity, and can be effective to treat with inflammation and immunoregulatory abnormality is the disease of feature.The example of the disease that can be treated includes but not limited to rheumatoid arthritis, asthma, allergy, psoriasis, Crohn disease, systemic lupus erythematosus, multiple sclerosis, diabetes, cancer, glaucoma, osteoporosis, renal ischaemia, apoplexy, cerebral ischemia and nephritis.The invention still further relates to the Pharmaceutical composition that comprises one or more The compounds of this invention and with the method for such compounds for treating cancer, inflammation, immunomodulating disease and respiratory system disease.

Cannabined receptor belongs to G-G-protein linked receptor superfamily.They are classified as mainly at neuronic CB ₁Receptor and main CB in periphery ₂Receptor.CB ₁The effect of receptor is main relevant with the central nervous system, and CB ₂Receptor is considered to have the periphery effect relevant with bronchoconstriction, immunomodulating and inflammation.Therefore, selectivity CB ₂Receptor-binding agents estimate the disease of control and inflammation, immunomodulating and bronchoconstriction such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renal ischaemia, apoplexy, cerebral ischemia, nephritis, lung and inflammatory diseases of gastro-intestinal tract and respiratory passage diseases such as reversibility airway obstruction, chronic asthma and bronchitis (referring to, as R.G.Pertwee, Curr.Med.Chem.6 (8), (1999), has therapeutic use 635).

It is reported and had been found that and CB ₂All cpds acceptor interaction and/or that especially have the anti-inflammatory activity relevant with Cannabined receptor.Referring to, as United States Patent(USP) Nos. 5,338,753,5,462,960,5,532,237,5,925,768,5,948,777,5,990,170,6,013,648 and 6,017,919.

The invention summary

The invention provides the chemical compound represented by formula I or the pharmaceutically acceptable salt or the solvate of described chemical compound:

Wherein:

A is selected from phenyl, naphthyl, pyridine radicals, thienyl, thiazolyl, indyl, azaindolyl, quinolyl, isoquinolyl, pyrazinyl, pyridazinyl, furyl, pyrrole radicals, pyrimidine radicals, cinnolines base, quinazolyl, quinoxalinyl, phthalazinyl, benzofuranyl and benzothienyl;

B is selected from formula B1-B7:

Or

Each Y independently is selected from-(C (R ⁷) ₂) _p-,-O-(C (R ⁷) ₂) _q-,-(C (R ⁷) ₂) _q-O-,-S-(C (R ⁷) ₂) _r-,-(C (R ⁷) ₂) _rS-,-S (O)-(C (R ⁷) ₂) _r-,-(C (R ⁷) ₂) _r-S (O)-,-S (O ₂)-(C (R ⁷) ₂) _r-,-(C (R ⁷) ₂) _r-S (O ₂)-,-N (R ⁷)-(C (R ⁷) ₂) _rWith-(C (R ⁷) ₂) _r-N (R ⁷)-;

Each Z independently is selected from-(C (R ⁷) ₂) _p-,-O-(C (R ⁷) ₂) _q-,-(C (R ⁷) ₂) _q-O-,-S-(C (R ⁷) ₂) _r-,-(C (R ⁷) ₂) _r-S-,-S (O)-(C (R ⁷) ₂) _r-,-(C (R ⁷) ₂) _r-S (O)-,-S (O ₂)-(C (R ⁷) ₂) _r,-(C (R ⁷) ₂) _r-S (O ₂)-,-N (R ⁷)-(C (R ⁷) ₂) _r-and-(C (R ⁷) ₂) _r-N (R ⁷)-;

P is the integer of 1-3;

Q is 1 or 2;

R is the integer of 0-2;

S is 0 or 1, and wherein when s was 0, Z was that covalent bond and B have two ring structures;

L1 be selected from covalent bond ,-(C (R ⁷) ₂) _p-,-C (O)-,-C (O) O-,-OC (O)-,-CH (OR ⁷)-,-S (O ₂)-,-S (O)-,-S-,-O-,-N (R ⁷)-,-C (O) N (R ⁷)-,-N (R ⁷) C (O)-,-OC (O) N (R ⁷)-,-N (R ⁷) C (O) O-,-N (R ⁷) C (O) N (R ⁷)-,-CF ₂-and-C (=N-OR ⁷)-;

L ²Be selected from-(C (R ⁷) ₂) _p-,-C (O)-,-C (O) O-,-OC (O)-,-CH (OR ⁷)-,-S (O ₂)-,-S (O)-,-S-,-O-,-N (R ⁷)-,-C (O) N (R ⁷)-, N (R ⁷) C (O)-,-OC (O) N (R ⁷)-,-N (R ⁷) C (O) O-,-N (R ⁷) C (O) N (R ⁷)-,-CF ₂-and-C (=N-OR ⁷)-;

L ³Be selected from covalent bond ,-C (R ⁷) ₂-,-C (O)-,-C (O) O-,-OC (O)-,-CH (OR ⁷)-,-S (O ₂)-,-S (O)-,-S-,-O-,-N (R ⁷)-,-C (O) N (R ⁷)-, N (R ⁷) C (O)-,-CF ₂-and-C (=N-OR ⁷)-;

R ¹Be selected from H, alkyl ,-CF ₃,-Si (alkyl) t (aryl) _3-t, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl,

Wherein each described alkyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl can be and unsubstitutedly or independent replaced by one or more substituent groups that independently are selected from following groups that can be identical or different: halogen ,-OH, alkoxyl, halogenated alkoxy, alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-N (R ⁷) ₂,-C (O) R ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) N (R ⁷) ₂,-N (R ⁷) C (O) R ⁷,-N (R ⁷) C (O) OR ⁷,-N (R ⁷) C (O) N (R ⁷) ₂,-NO ₂,-CN ,-S (O ₂) R ⁷,-S (O ₂) N (R ⁷) ₂With-N (R ⁷) C (=N-CN) NHR ⁷

T is the integer of 0-3;

R ²Be selected from H ,-OH, halogen ,-N (R ⁷) ₂, alkoxyl, halogenated alkoxy, alkyl, haloalkyl, cycloalkyl, cycloalkyl oxy, Heterocyclylalkyl, Heterocyclylalkyl oxygen base, aryl, aryloxy, heteroaryl and heteroaryl oxygen base,

Wherein each described alkoxyl, halogenated alkoxy, alkyl, haloalkyl, cycloalkyl, cycloalkyl oxy, Heterocyclylalkyl, Heterocyclylalkyl oxygen base, aryl, aryloxy, heteroaryl and heteroaryl oxygen base can be and unsubstitutedly or independent replaced by one or more substituent groups that independently are selected from following groups that can be identical or different: halogen ,-OH, alkoxyl, halogenated alkoxy, alkyl, haloalkyl, cycloalkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-N (R ⁷) ₂,-C (O) R ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) N (R ⁷) ₂,-N (R ⁷) C (O) R ⁷,-N (R ⁷) C (O) OR ⁷,-N (R ⁷) C (O) N (R ⁷) ₂,-NO ₂,-CN ,-S (O ₂) R ⁷,-S (O ₂) N (R ⁷) ₂With-N (R ⁷) C (=N-CN) NHR ⁷

N is the integer of 0-4;

R ³And R ⁴Identical or different, and be H or alkyl independently,

Wherein said alkyl can be and unsubstitutedly or independent replaced by one or more substituent groups that independently are selected from following groups that can be identical or different: halogen ,-OH, alkoxyl, halogenated alkoxy, alkyl, haloalkyl, alkoxyl, cycloalkyl, cycloalkyl oxy, Heterocyclylalkyl, Heterocyclylalkyl oxygen base, aryl, aryloxy, heteroaryl, heteroaryl oxygen base ,-N (R ⁷) ₂,-C (O) R ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) N (R ⁷) ₂,-N (R ⁷) C (O) R ⁷,-N (R ⁷) C (O) OR ⁷,-NR ⁷C (O) N (R ⁷) ₂,-NO ₂,-CN ,-S (O ₂) R ⁷,-S (O ₂) N (R ⁷) ₂With-N (R ⁷) C (=N-CN) NHR ⁷Or

If B is one of formula B4-B7, then R ³And R ⁴Form carbonyl with their carbon atom of connection shown in the formula B4-B7; Or

R ³And R ⁴Form non-armaticity ring system with their carbon atom of connection shown in the formula B4-B7,

Wherein said cycloalkyl or heterocycloalkyl ring can be and unsubstitutedly or independent replaced by one or more substituent groups that independently are selected from following groups that can be identical or different: halogen ,-OH, alkoxyl, halogenated alkoxy, alkyl, haloalkyl, alkoxyl, cycloalkyl, cycloalkyl oxy, Heterocyclylalkyl, Heterocyclylalkyl oxygen base, aryl, aryloxy, heteroaryl, heteroaryl oxygen base ,-N (R ⁷) ₂,-C (O) R ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) N (R ⁷) ₂,-N (R ⁷) C (O) R ⁷,-N (R ⁷) C (O) OR ⁷,-NR ⁷C (O) N (R ⁷) ₂,-NO ₂,-CN ,-S (O ₂) R ⁷,-S (O ₂) N (R ⁷) ₂With-N (R ⁷) C (=N-CN) NHR ⁷

R ⁵And R ⁶Identical or different, independently be selected from separately: H, alkyl, haloalkyl ,-CF ₃, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl,

Wherein each described alkyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl can be and unsubstitutedly or independent replaced by one or more substituent groups that independently are selected from following groups that can be identical or different: halogen ,-OH, alkoxyl, halogenated alkoxy, alkyl, haloalkyl, alkoxyl, cycloalkyl, cycloalkyl oxy, Heterocyclylalkyl, Heterocyclylalkyl oxygen base, aryl, aryloxy, heteroaryl, heteroaryl oxygen base ,-N (R ⁷) ₂,-C (O) R ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) N (R ⁷) ₂,-N (R ⁷) C (O) R ⁷,-N (R ⁷) C (O) OR ⁷,-N (R ⁷) C (O) N (R ⁷) ₂,-NO ₂,-CN ,-S (O ₂) R ⁷,-S (O ₂) N (R ⁷) ₂With-N (R ⁷) C (=N-CN) NHR ⁷

Each R ⁷Independently be selected from H, alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein each described alkyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl can be and unsubstitutedly or independent replaced by one or more substituent groups that independently are selected from following groups that can be identical or different: halogen ,-OH, alkoxyl, halogenated alkoxy, alkyl, haloalkyl, alkoxyl, cycloalkyl, cycloalkyl oxy, Heterocyclylalkyl, Heterocyclylalkyl oxygen base, aryl, aryloxy, heteroaryl and heteroaryl oxygen base;

X independently be selected from H, halogen, alkyl, alkoxyl, thiazolinyl, alkene oxygen base, alkynyl, alkynyloxy group, cycloalkyl, cycloalkyl oxy, Heterocyclylalkyl, Heterocyclylalkyl oxygen base, aryl, aryloxy, heteroaryl, heteroaryl oxygen base ,-OH, OR ⁷,-C (O) OR ⁷,-OC (O) R ⁷-,-N (R ⁷) ₂,-N (R ⁷) C (O) R ⁷,-N (R ⁷) C (O) OR ⁷,-NO ₂With-CN,

Wherein each described alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl can be and unsubstitutedly or independent replaced by one or more substituent groups that independently are selected from following groups that can be identical or different: halogen ,-OH, alkoxyl, halogenated alkoxy, alkyl, haloalkyl, alkoxyl, cycloalkyl, cycloalkyl oxy, Heterocyclylalkyl, Heterocyclylalkyl oxygen base, aryl, aryloxy, heteroaryl, heteroaryl oxygen base ,-N (R ⁷) ₂,-C (O) R ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) N (R ⁷) ₂,-N (R ⁷) C (O) R ⁷,-N (R ⁷) C (O) OR ⁷,-N (R ⁷) C (O) N (R ⁷) ₂,-NO ₂,-CN ,-S (O ₂) R ⁷,-S (O ₂) N (R ⁷) ₂With-N (R ⁷) C (=N-CN) NHR ⁷Or

When A was selected from pyridine radicals, thienyl, thiazolyl, indyl, azaindolyl, quinolyl, isoquinolyl, pyrazinyl, pyridazinyl, pyrrole radicals, pyrimidine radicals, cinnolines base, quinazolyl, quinoxalinyl, phthalazinyl and benzothienyl, X can be oxide;

-N (R ⁵)-L ³-R ⁶Can choose the formation ring system wantonly; With

M is the integer of 0-4.

Chemical compound of the present invention can be used as cannabinoid receptor ligand.Described chemical compound can have anti-inflammatory activity and/or immunoregulatory activity, can be effective to treat various medical conditions, comprises, as T-cell lymphoma,cutaneous; Rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, glaucoma, diabetes, sepsis, shock, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal diseases, scleroderma, osteoporosis, renal ischaemia, myocardial infarction, apoplexy, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, CFA (cryptogenic fibrosing aveolitis), psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, the pollinosis, Crohn disease, inflammatory bowel, the reversibility airway obstruction, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD) or bronchitis.Should be appreciated that chemical compound of the present invention can be effective to treat top one or more listed diseases.

The present invention also provides the Pharmaceutical composition that comprises one or more formulas I chemical compound.Pharmaceutical composition of the present invention also can be chosen wantonly and comprise one or more formulas I chemical compound and one or more pharmaceutical acceptable carriers, and/or one or more second medicines (second agents), described second medicine can identical or mutual difference, independently is selected from the moist medicine of wind resistance (DMARDS), nonsteroidal antiinflammatory drug (NSAIDS), cox 2 inhibitor, COX-1 inhibitor, immunosuppressant, biological response modifiers (BRMs), interferon beta 1a, interferon beta 1b, acetic acid glatiramer and other anti-inflammatory drug of alleviating disease.

Except in operation embodiment or other situation about indicating, the numeral of amount that is used for all expression compositions, reaction conditions etc. of description and claim under any circumstance all should be understood that to be modified by term " about ".

Detailed Description Of The Invention

In one embodiment, the invention provides chemical compound or its pharmaceutically acceptable salt or the solvate of formula I, a plurality of parts among its Chinese style I as mentioned above.In another embodiment of formula I chemical compound, A is represented by one of following formula A1-A5:

In other embodiments of formula I chemical compound, A is represented by formula A1.

In other embodiments of formula I chemical compound, A is represented by formula A2.

In other embodiments of formula I chemical compound, A is represented by formula A3.

In other embodiments of formula I chemical compound, A is represented by formula A4.

In other embodiments of formula I chemical compound, A is represented by formula A5.

In another embodiment of formula I chemical compound, B is represented by one of formula B1-B3.

In another embodiment of formula I chemical compound, B is represented by formula B1.

In another embodiment of formula I chemical compound, B is represented by one of formula B4-B7.

In another embodiment of formula I chemical compound, B is represented by formula B4.

In another embodiment of formula I chemical compound, B is represented by formula B5.

In another embodiment of formula I chemical compound, L ¹For-C (R ⁷) ₂,-C (O)-,-S (O)-,-C (O) O-or-S (O ₂)-.

In another embodiment of formula I chemical compound, L ²For-C (R ⁷) ₂-,-C (O)-,-S (O)-or-S (O ₂)-.

In another embodiment of formula I chemical compound, L ³For-C (O)-,-C (R ⁷) ₂Or-S (O ₂)-.

In another embodiment of formula I chemical compound, R ¹Be selected from alkyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein each described alkyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl can be and unsubstitutedly or independent replaced by one or more substituent groups that independently are selected from following groups that can be identical or different: halogen, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl ,-N (R ⁷) ₂,-CN, (C ₁-C ₆) alkoxyl and-OH.

In another embodiment of formula I chemical compound, R ²For H ,-OH, halogen ,-N (R ⁷) ₂, CF ₃, alkoxyl, alkyl, (C ₁-C ₆) haloalkyl, (C ₃-C ₅) cycloalkyl or-CH ₂-(C ₃-C ₅) cycloalkyl.

In another embodiment of formula I chemical compound, R ³And R ⁴Identical or different, and be H or (C independently ₁-C ₆) alkyl.

In another embodiment of formula I chemical compound, R ⁵Be H or (C ₁-C ₆) alkyl.

In another embodiment of formula I chemical compound, R ⁶Be H, (C ₁-C ₆) alkyl, (C ₃-C ₅) cycloalkyl or haloalkyl.

In another embodiment of formula I chemical compound, R ⁷Be H or (C ₁-C ₆) alkyl.

In another embodiment of formula I chemical compound, R ⁸Be H or (C ₁-C ₆) alkyl.

In another embodiment of formula I chemical compound, X independently is selected from H, halogen, alkyl, haloalkyl, (C ₃-C ₅) cycloalkyl ,-OH, alkoxyl, halogenated alkoxy and-CN.

In other embodiments of formula I chemical compound, B is represented that by formula B1 Y is-(C (R ⁷) ₂) _p-and p be the integer of 1-3.

In other embodiments of formula I chemical compound, B is represented by formula B1, and Y is-CH ₂-.

In other embodiments of formula I chemical compound, B is represented by formula B4, and s=0.

In other embodiments of formula I chemical compound, B is represented that by formula B5 s=2 and Z are-CH ₂-.

In other embodiments of formula I chemical compound, A is by one of formula A1-A5 expression, and B is represented by formula B1-B3.

In other embodiments of formula I chemical compound, A is by one of formula A1-A5 expression, and B is represented by one of formula B4-B7.

In other embodiments of formula I chemical compound, L ¹, L ²And L ³Independently be-S (O separately ₂)-or-CH ₂-.

In other embodiments of formula I chemical compound, R ¹Be selected from fluorophenyl, pyridine radicals, Trifluoromethoxyphen-l and methoxyphenyl.

In other embodiments of formula I chemical compound, R ²Be H.

In other embodiments of formula I chemical compound, R ³And R ⁴Be H.

In other embodiments of formula I chemical compound, R ³And R ⁴Form carbonyl with the carbon that connects them.

In other embodiments of formula I chemical compound, R ⁵Be H.

In other embodiments of formula I chemical compound, R ⁶Be selected from-CH ₃,-CF ₃And cyclopropyl.

In other embodiments of formula I chemical compound, m=1, and X be selected from H ,-CH ₃, 2-propyl group, F, Cl, Br ,-CF ₃,-OCH ₃With-OCF ₃

In the another embodiment of formula I chemical compound, chemical compound of the present invention is represented by II-XIX:

Wherein in formula II-XIX, X be selected from H, F, Cl, Br ,-CH ₃,-CF ₃,-OCH ₃,-OCF ₃,-OH and-CN;

R ¹Be selected from 2-fluorophenyl, 2-pyridine radicals, 4-methoxyphenyl and 4-Trifluoromethoxyphen-l;

R ²Be H or ethyl; With

R ⁶Be selected from methyl, trifluoromethyl and cyclopropyl.

In other embodiments again, the invention provides the Pharmaceutical composition that comprises one or more formulas I chemical compound and one or more pharmaceutical acceptable carriers.

In other embodiments again, the invention provides the Pharmaceutical composition that comprises one or more formulas I chemical compound and one or more second medicines and one or more pharmaceutical acceptable carriers.

In other embodiments again, the invention provides method with compounds for treating cancer, inflammatory diseases, immunomodulating disease and/or the respiratory system disease of one or more formulas I.

Following definition is used for herein, or is that those of skill in the art are known.Except as otherwise noted, following definition is applicable to entire description and claim.The commutative use of chemical name, common name and chemical constitution is to describe identical structure.Except as otherwise noted, no matter these terms be use separately or with other term coupling, these definition all are suitable for.Therefore, for example definition " alkyl " is applicable to " alkyl ", equally also is applicable to " alkyl " part of " hydroxy alkyl ", " haloalkyl ", " alkoxyl " etc.

Be opposite situation unless learn in addition, state or demonstrate, otherwise the junction point of the many terms substituent group that is connected with agent structure many terms of single part (lump together expression) is continuous for the term of the last name by many terms.For example, the cycloalkyl-alkyl substituent group links to each other with precursor structure (as, cycloalkyl-alkyl-precursor structure) for " alkyl " by substituent group back part.

" patient " comprises humans and animals.

" mammal " is meant people and the moving class animal of other suckling.

" alkyl " is meant unit price aliphatic hydrocarbon groups or base, and it can be considered to lose a hydrogen evolution by alkane.Alkyl can be straight or branched, can comprise about 20 carbon atoms of about 1-in the chain.Comprise about 12 carbon atoms of about 1-in the preferred alkyl chain.Comprise about 6 carbon atoms of about 1-in the preferred alkyl chain.

Term when mentioning alkyl " side chain " is meant that one or more low alkyl groups such as methyl, ethyl or propyl group link to each other with straight chained alkyl.

" low alkyl group " is meant the alkyl that has about 6 carbon atoms of about 1-in the chain." low alkyl group " can be straight or branched.

Term " replace alkyl " is meant the alkyl that can be replaced by one or more substituent groups, each substituent group can be identical or different, and each substituent group can independently be selected from halogen, alkyl, thiazolinyl, alkynyl, haloalkyl ,-OH, halogenated alkoxy, alkoxyl, cycloalkyl, cycloalkyl oxy, Heterocyclylalkyl, Heterocyclylalkyl oxygen base, aryl, aryloxy, heteroaryl, heteroaryl oxygen base ,-N (R ⁷) ₂,-C (O) R ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) N (R ⁷) ₂,-N (R ⁷) C (O) R ⁷,-N (R ⁷) C (O) OR ⁷,-N (R ⁷) C (O) N (R ⁷) ₂,-NO ₂,-CN ,-S (O ₂) R ⁷,-S (O ₂) N (R ⁷) ₂With-N (R ⁷) C (=N-CN) NHR ⁷, " R wherein ⁷" as above-mentioned definition.The limiting examples of suitable alkyl comprises methyl, ethyl, n-pro-pyl, isopropyl and the tert-butyl group.

" thiazolinyl " is meant unsaturated aliphatic hydrocarbon group or the base with at least one carbon-to-carbon double bond, and it can be considered to lose a hydrogen evolution by alkene.Thiazolinyl can be straight or branched, can comprise about 15 carbon atoms of 2-in the chain.Have about 12 carbon atoms of 2-in the preferred alkenylene chain, more preferably have about 6 carbon atoms of 2-in the chain.

Term when mentioning thiazolinyl " side chain " is meant that one or more low alkyl groups such as methyl, ethyl or propyl group link to each other with straight-chain alkenyl.

" alkynyl " is meant non-armaticity hydrocarbyl group or the base with at least one carbon-to-carbon triple bond, and it can be considered to lose a hydrogen evolution by alkynes.That alkynyl can be straight chain or side chain, have about 15 carbon atoms of 2-in the chain.Have about 12 carbon atoms of 2-in the preferred alkynyl chain, more preferably have about 4 carbon atoms of 2-in the chain.

Term when mentioning alkynyl " side chain " is meant that one or more low alkyl groups such as methyl, ethyl or propyl group link to each other with straight-chain alkynyl.

" aryl " is meant armaticity monocycle or multi-ring group, and it can be considered to lose a hydrogen evolution by armaticity monocycle or polycyclic hydrocarbon.Aryl can comprise about 14 carbon atoms of about 6-in ring, about 10 carbon atoms of preferably about 6-.Aryl can be chosen wantonly by one or more " ring system substituent group " and replace, and it can be identical or different, as give a definition.The non-limiting example of suitable aryl comprises phenyl and naphthyl.

" ring system " be meant armaticity, part is unsaturated or complete saturated ring, wherein all annular atomses are carbon, or one or more annular atoms is the element of carbon, as nitrogen, oxygen and sulfur.Ring system can comprise about 14 annular atomses of 3-, about 10 annular atomses of preferably about 5-, more preferably from about 5-6 annular atoms.Ring system can be chosen wantonly by one or more identical or different " ring system substituent group " and replace.Ring system can comprise cycloalkyl defined herein, Heterocyclylalkyl, aryl or heteroaryl ring, and the undersaturated cycloalkyl of part or heterocycloalkyl ring (as, cyclohexenyl group, thiazolinyl etc.).

" non-aromatic ring system " is meant any ring system defined above, but do not comprise aryl or heteroaryl ring.

" heteroaryl " is meant armaticity monocycle or multi-ring ring system, and it can be considered to one or more, and carbon atom on the armaticity hydrocarbon ring do not form for the element of carbon such as nitrogen, oxygen and sulfur are removed and/or replaced.Heteroaryl can comprise about 14 annular atomses of about 5-, about 10 annular atomses of preferably about 5-, more preferably from about about 6 annular atomses of 5-.Heteroaryl can be chosen wantonly by one or more " ring system substituent groups " as giving a definition that can be identical or different and replace.Prefix " azepine ", " oxa-" or " thia " before the heteroaryl root name claims are meant that respectively at least one annular atoms is nitrogen, oxygen or sulfur.Nitrogen-atoms on the heteroaryl can be chosen wantonly and be oxidized to corresponding N-oxide.The limiting examples of suitable heteroaryl comprises pyridine radicals, pyrazinyl, furyl, thienyl, pyrimidine radicals, different _ the azoles base, isothiazolyl, _ azoles base, thiazolyl, pyrazolyl, the furazan base, pyrrole radicals, triazolyl, 1,2, the 4-thiadiazolyl group, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo [1,2-a] pyridine radicals, imidazo [2,1-b] thiazolyl, benzofuranyl, indyl, azaindolyl, benzimidazolyl, benzothienyl, quinolyl, imidazole radicals, the thienopyridine base, quinazolyl, the Thienopyrimidine base, pyrrolopyridinyl, imidazopyridyl, isoquinolyl, the benzo-aza indyl, 1,2, the 4-triazine radical, benzothiazolyl, pyridazinyl, pyrimidine radicals, cinnolines base etc.

Should note tautomeric form, as following part:

With

Be considered to equal in certain embodiments of the invention.

" cycloalkyl " be meant non-armaticity (promptly aliphatic) single-or multi-ring ring system, comprise about 10 carbon atoms of about 3-on the ring, about 10 carbon atoms of preferably about 5-.Preferred cycloalkyl ring comprises about 7 carbon atoms of about 5-.Cycloalkyl can choose wantonly by can be identical or different replace as one or more " the ring system substituent group " given a definition.The limiting examples of suitable monocyclic cycloalkyl comprises cyclopropyl, cyclopenta, cyclohexyl, suberyl etc.The limiting examples of suitable polycyclic naphthene base comprises 1-naphthalane base (decalinyl), norborny (norbomyl), adamantyl (adamantyl) etc.

" Heterocyclylalkyl " is meant non-armaticity monocycle or multi-ring ring system, comprises about 10 annular atomses of 3-, about 10 annular atomses of preferably about 5-, and wherein the one or more atoms on the ring system are the element of carbon, for example nitrogen, oxygen or sulfur.If be the element of carbon more than one annular atoms, then non-carboatomic ring atom can be identical or different.But Heterocyclylalkyl does not comprise the ring system that has adjacent oxygen and/or sulphur atom in the ring system.Preferred Heterocyclylalkyl ring system comprises about 6 annular atomses of about 5-.Prefix " azepine ", " oxa-" or " thia " before the Heterocyclylalkyl root name claims are meant that at least one annular atoms is respectively nitrogen, oxygen or sulphur atom.Any-NH-in the heterocycloalkyl ring can be protected form, as-N (Boc)-,-N (CBz)-,-N (Tos)-group etc.; This protected-the NH--group also is considered to part of the present invention.Heterocyclylalkyl can be chosen wantonly by one or more " ring system substituent groups " as defined above that can be identical or different and replace.Nitrogen on the Heterocyclylalkyl or sulphur atom can be chosen wantonly and be oxidized to corresponding N-oxide, S-oxide or S, the S-dioxide.The limiting examples of suitable monocyclic heterocycles alkyl ring comprises piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thio-morpholinyl, thiazolidinyl, 1,4-dioxane base, tetrahydrofuran base, tetrahydro-thienyl etc.

Should note comprising in the heteroatomic ring system, on the carbon atom adjacent, not have hydroxyl with N, O or S of the present invention.In addition, on the carbon atom adjacent, there are not N or S group with other hetero atom.Therefore, for example, in the ring below:

Do not have-OH directly is connected in and is labeled as on 2 and 5 the carbon, and can not be hetero atom at 2 and 5 annular atoms.

" cycloalkyl oxy " is meant that cycloalkyl links to each other with parent fraction by ether oxygen as defined above.The limiting examples of suitable cycloalkyl oxy is a cyclohexyl oxygen base:

Similarly, Heterocyclylalkyl oxygen base is meant that Heterocyclylalkyl links to each other with parent fraction by ether oxygen as defined above.

" halogen " or " halo " is meant fluorine, chlorine, bromine or iodine.Preferred halogen is fluorine, chlorine or bromine, more preferably fluorine and chlorine.

" ring system substituent group " is meant the substituent group of the available hydrogen that being considered to of linking to each other with armaticity or non-armaticity ring system fastens as D-loop.Ring system can be replaced by one or more ring system substituent groups.If ring system is replaced by two or more ring system substituent groups; then described ring system substituent group can be identical or different, independently is selected from alkyl separately; thiazolinyl; alkynyl; aryl; heteroaryl; aralkyl; alkylaryl; heteroarylalkyl; the heteroaryl thiazolinyl; the heteroaryl alkynyl; miscellaneous alkyl aryl; hydroxyl; hydroxy alkyl; alkoxyl; aryloxy; aralkoxy; acyl group; aroyl; halogen; nitro; cyano group; carboxyl; alkoxy carbonyl; the aryloxy carbonyl; aromatic alkoxy carbonyl; alkyl sulphonyl; aryl sulfonyl; heteroarylsulfonyl; alkyl sulfenyl (alkylthio); artyl sulfo (arylthio); heteroaryl sulfenyl (heteroarylthio); aromatic alkyl sulfurio (aralkylthio); heteroarylalkyl sulfenyl (heteroaralkylthio); cycloalkyl; Heterocyclylalkyl;-C (=N-CN)-NH ₂,-C (=NH)-NH ₂,-C (=NH)-NH (alkyl), L ¹L ²N-, L ¹L ²The N-alkyl-, L ¹L ²NC (O)-, L ¹L ²NSO ₂-and-SO ₂NL ¹L ², L wherein ¹And L ²Can be identical or different, independently be selected from hydrogen, alkyl, aryl, cycloalkyl and aralkyl." ring system substituent group " also can comprise can be considered to the single part that the while D-loop is fastened two hydrogen (hydrogen on each carbon) on two adjacent carbon atoms.The example of such part comprise methylenedioxy, ethylenedioxy ,-C (CH ₃) ₂-etc., it links to each other with ring and forms following structure:

With

" aralkyl " or " aryl alkyl " is meant wherein aryl and the foregoing aryl-alkyl of alkyl-group.The preferred aryl groups alkyl comprises the low alkyl group that is replaced by at least one aryl.The limiting examples of suitable aryl alkyl comprises benzyl, 2-phenethyl and menaphthyl (naphthalenylmethyl).Link to each other with parent fraction by alkyl.

" alkylaryl " is meant wherein alkyl and the foregoing alkyl-aryl of aryl-group.Preferred alkylaryl comprises the aryl that is replaced by at least one low alkyl group.The limiting examples of suitable alkylaryl comprises tolyl.Link to each other with parent fraction by aryl.

" heteroarylalkyl " or " heteroaryl alkyl " is meant wherein heteroaryl and the foregoing heteroaryl-alkyl of alkyl-group.Preferred heteroaryl alkyl comprises low alkyl group.The limiting examples of suitable heteroaryl alkyl comprises pyridylmethyl and quinoline-3-ylmethyl.Heteroaryl alkyl links to each other with parent fraction by its moieties.

" heteroaryl thiazolinyl " is meant wherein heteroaryl and the aforesaid heteroaryl-thiazolinyl of thiazolinyl-group.Heteroaryl links to each other with parent fraction by the alkenyl part in the heteroaryl thiazolinyl.

" heteroaryl alkynyl " is meant wherein heteroaryl and the aforesaid heteroaryl-alkynyl of alkynyl-group.Heteroaryl links to each other with parent fraction by the part of the alkynyl in the heteroaryl alkynyl.

" miscellaneous alkyl aryl " is meant wherein alkyl and the aforesaid alkyl-heteroaryl of heteroaryl-group.The limiting examples of miscellaneous alkyl aryl is a picolyl.Moieties links to each other with parent fraction by the heteroaryl moieties of miscellaneous alkyl aryl.

" hydroxy alkyl " is meant wherein alkyl HO-alkyl-group as defined above.Preferred hydroxy alkyl comprises low alkyl group.The limiting examples of suitable hydroxy alkyl comprises hydroxymethyl and 2-hydroxyethyl.

" acyl group " be meant wherein alkyl and the foregoing H-C of cycloalkyl (O)-, alkyl-C (O)-or cycloalkyl-C (O)-group.Acyl group links to each other with parent fraction by carbonyl.Preferred acyl group comprises low alkyl group.The limiting examples of suitable acyl group comprises formoxyl, acetyl group and propiono (propanoyl).

" aroyl " is meant the wherein foregoing aryl-C of aryl (O)-group.Aroyl links to each other with parent fraction by carbonyl.The limiting examples of suitable aroyl comprises benzoyl and 1-naphthoyl.

" alkoxyl " is meant the wherein foregoing alkyl of alkyl-O-group.The limiting examples of suitable alkoxyl comprises methoxyl group, ethyoxyl, positive propoxy, isopropoxy and n-butoxy.Alkoxyl links to each other with parent fraction by ether oxygen.

" aryloxy " is meant the wherein foregoing aryl of aryl-O-group.The limiting examples of suitable aryloxy comprises phenoxy group and naphthoxy.Aryloxy links to each other with parent fraction by ether oxygen.

" aralkyl oxy " is meant the wherein foregoing aralkyl of aralkyl-O-group.The limiting examples of suitable aralkyl oxy comprises benzyl oxygen base and 1-or 2-naphthalene methoxyl group.Aralkyl oxy links to each other with parent fraction by ether oxygen.

" alkyl sulfenyl " is meant the wherein foregoing alkyl of alkyl-S-group.The limiting examples of suitable alkyl sulfenyl comprises methyl sulfenyl and ethyl sulfenyl.The alkyl sulfenyl links to each other with parent fraction by sulfur.

" artyl sulfo " is meant the wherein foregoing aryl of aryl-S-group.The limiting examples of suitable artyl sulfo comprises phenyl sulfenyl and naphthyl sulfenyl.Artyl sulfo links to each other with parent fraction by sulfur.

" aromatic alkyl sulfurio " is meant the wherein foregoing aralkyl of aralkyl-S-group.The limiting examples of suitable aromatic alkyl sulfurio is the benzyl sulfenyl.Aromatic alkyl sulfurio links to each other with parent fraction by sulfur.

" alkoxy carbonyl " is meant alkyl-O-C (O)-group.The limiting examples of suitable alkoxy carbonyl comprises methoxycarbonyl and ethoxy carbonyl.Alkoxy carbonyl links to each other with parent fraction by carbonyl.

" aryloxy carbonyl " is meant aryl-O-C (O)-group.The limiting examples of suitable aryloxy carbonyl comprises phenyloxycarbonyl and naphthoxy carbonyl.The aryloxy carbonyl links to each other with parent fraction by carbonyl.

" aromatic alkoxy carbonyl " is meant aralkyl-O-C (O)-group.The limiting examples of suitable aromatic alkoxy carbonyl is a benzyl oxygen base carbonyl.Aromatic alkoxy carbonyl links to each other with parent fraction by carbonyl.

" alkyl sulphonyl " is meant alkyl-S (O ₂)-group.Preferred alkyl sulphonyl comprises the group of low alkyl group for alkyl wherein.Alkyl sulphonyl links to each other with parent fraction by sulfonyl.

" aryl sulfonyl " is meant aryl-S (O ₂)-group.Aryl sulfonyl links to each other with parent fraction by sulfonyl.

" halogen alkyl " or " haloalkyl " are meant that wherein at least one hydrogen is by the metathetical alkyl of halogen.

" assorted alkyl " is meant at least one carbon atom in its medium chain that comprises 1-12 carbon atom by the metathetical straight or branched alkyl chain of hetero atom, and wherein said hetero atom independently is selected from nitrogen, oxygen or sulfur.

The term azaindolyl be meant a carbon on the phenyl ring wherein by the metathetical indyl of nitrogen as shown in the following limiting examples:

The term azaindolyl also comprises tautomeric form, shown in following limiting examples:

When not spelling out spatial chemistry in the structure, described structure comprises the mixture (as, racemic mixture) of all three-dimensional chemical configurations with the connection indicated (as, all possible enantiomer) and these stereoisomers.For example,

Be meant

And/or

Or its racemic mixture.

Term " replace " is meant that the one or more hydrogen that connect on specified atom or the group are selected from the group displacement of specifying group, and condition is to be no more than normally tiring of specified atom under the present circumstances or group, and described replacement produces stable chemical compound.Only unite under the situation that produces stable compound, the uniting of substituent group and/or variable be only permission described." stable compound " or " rock-steady structure " is meant that chemical compound is enough solid, so that can isolate from reactant mixture to effective purity, and makes effective medicine.

Term " the optional replacement " is meant can be by special groups, base or replacement partly, but optional.

Should notice that any hetero atom tire that satisfies in this paper text, embodiment, embodiment and form is assumed to be that having enough hydrogen atoms satisfies it and tire.

When the functional group in the chemical compound was called as " shielded ", this was meant that this group exists to prevent that this chemical compound from shielded site unnecessary side reaction taking place under special reaction condition with the form of modifying.Those of ordinary skills can understand suitable blocking group; but also reference standard textbook such as T.W.Greene et al, Protective Groups in Organic Synthesis (1991), Wiley; New York all is attached to it herein by reference at this.

Except as otherwise noted, when any variable (as, aryl, heterocycle, R ⁷Deng) when occurring more than one time in any structure or structural formula, its definition is independent of it in other definition when occurring at every turn at every turn when occurring.

The all terms " compositions " of this paper comprise the product of the combination of any special component that comprises any specified quantitative, and from the combination of any special component of any specified quantitative directly, the spawn that forms indirectly.

The prodrug and the solvate of The compounds of this invention are also contained in herein.Term used herein " prodrug " is meant the chemical compound into prodrug, produces formula I compound or its salt of the present invention and/or solvate by metabolism or the chemical conversion of chemical process experience when giving the patient.At T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S.Symposium Series and Bioreversible Carriers in DrugDesign, (1987) Edward B.Roche, ed., the discussion of relevant prodrug is provided among the American PharmaceuticalAssociation and Pergamon Press, and the both is attached to herein by reference.

" solvate " is meant the physical bond of The compounds of this invention and one or more solvent molecules.This physical bond relates to the ion and the covalent bond of various degree, comprises hydrogen bond.Solvate can be separated in some example, as in the lattice that is combined in crystalline solid when one or more solvent molecules the time." solvate " comprises solution phase and solvate that can be separated.The limiting examples of suitable solvate comprises ethanol compound, methanol compound etc." hydrate " is H for solvent molecule wherein ₂The solvate of O.

Except as otherwise noted, formula I chemical compound of the present invention mentioned in this article is understood to include its prodrug and solvate.

" effective dose " or " treatment effective dose " be meant can effectively the regulating of chemical compound of the present invention and compositions (as suppress, activate or in conjunction with) CB ₂Therefore receptor also produces the amount of required treatment, improvement, inhibition or preventive effect.

Chemical compound of the present invention (as, the chemical compound of the formula M-XIX of example in the following table 1) can form salt, this is also included within the scope of the present invention.Term used herein " salt " be meant the ackd salt that forms with inorganic and/or organic acid and with basic salt inorganic and/or that organic base forms.In addition, when formula I chemical compound of the present invention comprise simultaneously basic moiety as but be not limited to pyridine radicals, indyl or imidazole radicals and acidic moiety as but when being not limited to carboxylic acid, can form amphion (" inner salt "), it is also included within the term used herein " salt ".Although other salt is effective equally, preferred pharmacy can be accepted (be nontoxic, physiology can accept) salt.

Can by as the acid of formula I chemical compound and appropriate amount such as equivalent or alkali, carried out lyophilizing then and forms formula I chemical compound of the present invention as described therein in the precipitable medium that goes out of salt or react in aqueous medium at suitable medium.

Except as otherwise noted, when this paper mentions formula I chemical compound of the present invention, should be understood to include its salt.

The example of acid-addition salts (promptly by formula I chemical compound of the present invention is added the salt that suitable acid forms) comprises acetate, Ascorbate, benzoate, benzene sulfonate, bisulphate, borate, butyrate, citrate, camphorate, camsilate, fumarate, hydrochlorate, hydrobromate, hydriodate, lactate, maleate, mesylate, naphthalene sulfonate, nitrate, oxalate, phosphate, propionate, Salicylate, succinate, sulfate, tartrate, rhodanate, toluene fulfonate (being toluene fulfonate) etc.In addition, as at S.Berge et al, Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; P.Gould, International J.of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), AcademicPress, New York; And at orange paper (Food﹠amp; Drug Administration, Washington, D.C.on their website) in the acid that is considered to usually to be fit to from basic medicinally compound formation pharmaceutically effective salt all has been discussed, these documents all are attached to herein by reference at this.

The example of basic salt (promptly adding the salt that suitable alkali forms by formula I chemical compound mutually of the present invention) comprises ammonium salt, alkali metal salt such as sodium, lithium and potassium salt, alkali salt such as calcium and magnesium salt, the salt of organic base (as organic amine) such as dicyclohexylamine, tert-butylamine, and amino acid whose salt such as arginine, lysine etc.Basic salt also can comprise and carries out quaternary ammoniated the formula I chemical compound that contains the basic nitrogen group of the present invention and salt that form with alkylating reagent such as elementary alkyl halide (as methyl, ethyl and butyl chloride, bromide and iodide), dialkylsulfates (as dimethyl, diethyl and dibutyl sulfide acid esters), long-chain halogenide (as decyl, dodecyl and stearyl chloride, bromide and iodide), aralkyl halide (as benzyl and phenethyl bromination thing) and other.

These hydrochlorates and the alkali salt of promising pharmaceutically acceptable salt be included in the scope of the present invention, and for the purposes of the present invention, the free form that all bronsted lowry acids and bases bronsted lowry salt all are considered to corresponding compounds is what be equal to.

Formula I chemical compound and salt thereof, solvate and prodrug can its tautomeric form (as amide or imido-ether) exist.All these tautomeric forms all are parts of the present invention.

The all isomers (as stereoisomer, geometric isomer, optical isomer etc.) of formula I chemical compound (salt and the solvate that comprise the prodrug of salt, solvate and the prodrug of The compounds of this invention and The compounds of this invention), the isomer that exists as on different substituents, having asymmetric carbon atom, comprise enantiomerism form (itself even do not have also can exist under the situation of asymmetric carbon atom), rotational isomeric form, atropisomer and diastereo-isomerism form all within the scope of the invention, also comprise position isomer (as 4-pyridine radicals and 3-pyridine radicals).

The polymorphic of salt, solvate and the prodrug of formula I chemical compound and formula I chemical compound is also included within the present invention.

The single stereoisomer of formula I chemical compound can as, do not have other isomer basically, maybe can comprise two or more mixture of isomers.For example, chemical compound of the present invention can be the form of mixtures of racemic mixture or selected stereoisomer.

The chiral centre of The compounds of this invention can have S or the R configuration of recommending definition as IUPAC 1974.The use of term " salt ", " solvate " " prodrug " etc. is applicable to salt, solvate and the prodrug of enantiomer, stereoisomer, rotamer, tautomer, position isomer, racemic compound or the prodrug of The compounds of this invention too.

Listed exemplary compounds of the present invention (and/or its pharmaceutically acceptable salt, solvate or prodrug) in the Table I, for formula I, Table I has been listed R ¹, R ⁶,-A-X ,-B-N (R ⁵)-and X.R ⁵Be H, n=1, m=1, L ²For-S (O ₂)-.For clear, Table I has also been listed the X-N (R in A and the B structure partly ⁵)-, L ¹, L ²And L ³

Table I

(enantiomer refers to enantiomer in the following table, and recemic mixture refers to racemic mixture)

The present invention includes all isomers (as enantiomer) of the chemical compound of listing above and mixture of isomers (as, racemic mixture).As preparing isomer mixture from the isomer mixture of initiation material or by the reaction condition for preparing isomer products.Can prepare specific isomer by from isomer mixture, isolating specific isomer from isomer pure initiation material or employing known method (as adopting the chromatography of chiral stationary phase).

One aspect of the present invention relates to the Pharmaceutical composition of one or more The compounds of this invention (and/or its pharmaceutically acceptable salt, solvate or prodrug) that are included in the pharmaceutical acceptable carrier.Pharmaceutical composition of the present invention also can be chosen wantonly and comprise one or more other medicines.

Chemical compound of the present invention can be used as cannabinoid receptor ligand.Therefore, another aspect of the present invention relates to adjusting (suppressing or activation) patient's cannabinoid CB ₂The method of receptor, described method comprise and give the patient CB ₂One or more The compounds of this invention of receptor-regulated quantity.

The compounds of this invention can have anti-inflammatory activity and/or immunoregulatory activity, can be effective to treat cancer, inflammatory diseases, immunomodulating disease or respiratory system disease.For example, one or more chemical compounds of formula I can be effective to treat various medical conditions, comprise T-cell lymphoma,cutaneous, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, glaucoma, diabetes, sepsis, shock, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal diseases, scleroderma, osteoporosis, renal ischaemia, myocardial infarction, apoplexy, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, CFA, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, the pollinosis, Crohn disease, inflammatory bowel, the reversibility airway obstruction, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD) or bronchitis.Should be appreciated that chemical compound of the present invention can be effective to treat one or more listed diseases.

In addition, chemical compound of the present invention can with the altogether administration or unite use of second medicine, described second medicine as the moist medicine of wind resistance (DMARDS) of alleviating disease as methotrexate, azathioprine, leflunomide, penicillamine (pencillinamine), golden salt, mycophenolate, cyclophosphamide and other similar medicine.They also can be total to administration or unite use with one or more following medicines: nonsteroidal antiinflammatory drug (NSAIDS) is as piroxicam, naproxen, indomethacin, ibuprofen etc.; (its commodity Vioxx_ by name is (from Merck﹠amp for COX-2 selective depressant such as rofecoxib; Company, Whitehouse Station, NJ)) and celecoxib (its commodity are called Celebrex_ (from Pfizer Inc., New York, New York)); (its commodity are called Feldene_ (from Pfizer Inc., New York, NewYork)) for COX-1 inhibitor such as piroxicam; Immunosuppressant such as steroid, ciclosporin, tacrolimus, rapamycin, methotrexate etc.; (its commodity Enbrel_ by name is (from Wyeth-Ayerst as Embrel for biological response modifiers (BRMs), Philadelphia, PA)), (its commodity Remicade_ by name is (from Centocor for English husband monoclonal antibody, Inc., Malvern, PA)), IL-1 antagonist, anti-CD 40, anti--CD28, IL-10, anti--adhesion molecule etc.; And other anti-inflammatory drug such as p38 inhibitors of kinases, PDE4 inhibitor, tace inhibitor, chemokine receptor anagonists, (its commodity are called Thalomid_ (Celgene Corporation to Thalidomide, Warren, NJ)) and other micromolecule proinflammatory cytokine product inhibitor.The other medicines that The compounds of this invention can be total to administration or unite use comprise Anaprox_ (being naproxen sodium), Arava_ (being leflunomide), Arthrotec_ (being the combination of diclofenac and misoprostol), Azulfidine_ (being sulfasalazine), Aspirin_ (being aspirin), Cataflam_ (being diclofenac), Celestone_Soluspan_ (being betamethasone acetate and betamethasone dosium phosphate), Clinoril_ (being sulindac), Cortone Acetate_ (being cortisone acetate), Cuprimine_ (being penicillamine), Daypro_ (being oxaprozin), Decadron_ (being dexamethasone), Depen_ (being penicillamine), Depo-Medrol_ (being methylprednisolone acetate), Disalcid_ (being salsalate), Dolobid_ (being diflunisal), Naprosyn_ (being naproxen), Gengraf_ (being ciclosporin), Hydrocortone_ (being hydrocortisone), Imuran_ (being azathioprine), Indocin_ (being indomethacin), Lodine_ (being etodolac), Motrin_ (being ibuprofen), Myochrysine_ (being Kidon (Ono)), Nalfon_ (being fenopron), Naprelan_ (being naproxen sodium), Neoral_ (being ciclosporin), Orudis_ (being ketoprofen), Oruvail_ (being ketoprofen), Pediapred_ (being prednisolone), Plaquenil_ (being oxychloroquine), Prelone_ (being prednisolone), Relafen_ (being nabumetone), Solu-Medrol_ (being Urbason Solubile), Tolectin_ (being tolmetin sodium), Trilisate_ (being Choline magnesium trisalicylate) and Volataren_ (being diclofenac).Any preparation of name medicine above these comprise.

Again in addition, The compounds of this invention can be total to administration with the H1 antagonist or unite and use treatment pollinosis and/or asthma appropriate H 1 antagonist can be, as Claritin_ (being loratadine), Clarinex_ (being Desloratadine), Allegra_ (being fexofenadine hydrochloride) or Zyrtec_ (being cetirizine hydrochloride).

On the other hand, the invention provides the method for treatment rheumatoid arthritis.Described method comprises unites the chemical compound that gives The compounds of this invention and be selected from following kind: cox 2 inhibitor such as Celebrex_ or Vioxx_; COX-1 inhibitor such as Feldene_ (being piroxicam); Immunosuppressant such as methotrexate or ciclosporin; Steroid compound such as β-betamethasone; Anti-TNF-α chemical compound is as Enbrel_ or Remicade_; The chemical compound that is used for the treatment of rheumatoid arthritis of PDE IV inhibitor and other kind.

In addition, the invention provides the Pharmaceutical composition of treatment rheumatoid arthritis, described compositions comprises The compounds of this invention for the treatment of effective dose and the chemical compound that is selected from following kind: the chemical compound that is used for the treatment of rheumatoid arthritis of cox 2 inhibitor, COX-1 inhibitor, immunosuppressant, steroid compound, anti-TNF-α chemical compound and other kind, and pharmaceutical acceptable carrier.

Aspect other, the invention provides the method for treatment multiple sclerosis, described method comprises uniting and gives chemical compound of the present invention and be selected from following chemical compound: Avonex_ (being interferon beta-1a), Betaseron_ (being interferon beta-1b), Copaxone_ (being the acetic acid glatiramer) or other is used for the treatment of the chemical compound of multiple sclerosis.

In addition, the present invention also provides the compositions of treatment multiple sclerosis, described compositions comprises The compounds of this invention for the treatment of effective dose and the chemical compound that is selected from vonex_, Betaseron_, Copaxone_, or other is used for the treatment of the chemical compound of multiple sclerosis, and pharmaceutical acceptable carrier.

Again on the other hand, the invention provides the psoriatic method of treatment, described method comprises unites the chemical compound that gives chemical compound of the present invention and be selected from immunosuppressant, steroid compound and anti-TNF-α chemical compound.In one aspect, described immunosuppressant is methotrexate, leflunomide, sulfasalazine or ciclosporin, and described steroid compound is β-betamethasone, and described anti-TNF-α chemical compound is Enbrel_ or Remicade_.

In addition, the present invention relates to treat psoriatic Pharmaceutical composition, the The compounds of this invention that described compositions comprises effective dose be selected from immunosuppressant (as, methotrexate, leflunomide or ciclosporin), steroid compound (as, β-methasone) and anti-TNF-α chemical compound (as, Enbrel_ or Remicade_) chemical compound, and pharmaceutical acceptable carrier.

As mentioned above, the invention provides the Pharmaceutical composition that comprises these one or more The compounds of this invention and pharmaceutical acceptable carrier.Chemical compound of the present invention can the known any regular dosage form administration of this area disease those of skill in the art.Can by adopt conventional pharmaceutical can accept excipient and additive and routine techniques prepare the compositions that comprises The compounds of this invention (as, one or more chemical compounds of formula M-XIX and/or its pharmaceutically acceptable salt, solvate or prodrug are chosen wantonly and are mixed with one or more pharmaceutical acceptable carriers, excipient, additive etc.).But described pharmaceutical acceptable excipient and additive comprise nontoxic compatibility filler, binding agent, disintegrating agent buffer agent, antiseptic, antioxidant, lubricant, flavoring agent, thickening agent, coloring agent, emulsifying agent etc.

All route of administration include but not limited to parenteral, percutaneous, subcutaneous, intramuscular, Sublingual, suction, rectum and topical.Therefore, suitable administration unit form comprises oral form such as tablet, capsule, powder, cachet, granule and solution or suspensoid, Sublingual and buccal form administration, aerosol, implants, subcutaneous, intramuscular, vein, intranasal, ophthalmic, subcutaneous or rectally form.

When solid composite is prepared as tablet; can in micronize or non-micronized The compounds of this invention, add wetting agent such as sodium lauryl sulfate, mix with pharmaceutical carrier such as silicon dioxide, gelatin, starch, lactose, magnesium stearate, Pulvis Talci, arabic gum etc.Available sucrose, various polymer or other suitable material carry out coating to tablet.Can handle so that it has activity prolongation or that postpone tablet, so that discharge the effective ingredient of predetermined amount continuously or discharge at interval, as by adopting ion exchange resin etc. with preset time.

Can be by one or more chemical compounds of the present invention and diluent such as glycerol or glyceride be mixed, the soft or hard capsule of again the gained mixture being packed into obtains the preparation of capsule form.

The preparation of syrup or elixir form can comprise one or more chemical compounds of the present invention and other composition such as sweeting agent, as methyl hydroxybenzoate and propylparaben as antiseptic, flavoring agent and suitable color.

Water can disperse powder and granule can comprise one or more chemical compounds of the present invention with as dispersant, wetting agent or suspending agent such as polyvinylpyrrolidone, and sweeting agent and/or other flavoring agent.

The suppository that is used for rectally can comprise one or more chemical compounds of the present invention with as, at the fusible binding agent of rectal temperature such as cocoa butter or Polyethylene Glycol

But the available water system suspension that comprises one or more The compounds of this invention and pharmacology's compatibility dispersant and/or solubilizing agent such as propylene glycol and Polyethylene Glycol, normal isotonic saline solution or aseptic and injection carry out parenteral, intranasal or eye drops

Therefore, in order to prepare the intravenous aqueous pharmaceutical that is used for of one or more The compounds of this invention, can adopt cosolvent such as alcohols such as ethanol or ethylene glycol or Polyethylene Glycol or propylene glycol and hydrophilic surfactant active such as Tween_80.Can be by one or more The compounds of this invention be prepared the oily solution agent of intramuscular injection with triglyceride or glyceride solubilising.

Can prepare local administration preparation by one or more chemical compounds of the present invention are mixed emulsifiable paste, ointment or gel.

Can carry out percutaneous dosing by the patch that employing comprises the multilamellar patch of one or more The compounds of this invention and appropriate solvent or has a storage.

But can by comprise one or more The compounds of this invention and anhydrate sorbitol olein or oleic acid and Arcton 11, dichlorofluoromethane, dichlorotetra-fluoroethane or any other biology the compatibility propellant aerosol carry out inhalation.Perhaps, intake system also can comprise bonded one or more chemical compounds of the present invention of excipient optional and powder type.

Chemical compound of the present invention also can be chosen wantonly with one or more carriers or additive and be made into microcapsule or microsphere, as liposome.

In order to treat chronic disease, one or more chemical compounds of the present invention can be from the implants administration, and it can provide the prolongation of The compounds of this invention to discharge.The compositions that comprises The compounds of this invention also can be made into oil-based suspension or wait the microsphere suspension form of oozing medium matter.

The compounds of this invention is regulated patient's cannabinoid CB ₂The receptor and/or the daily dose for the treatment of above-mentioned disease or disease are the about 100mg/kg body weight of about 0.001-every day, are preferably the about 10mg/kg of about 0.001-.Therefore, for the average weight of 70kg, dosage level is the about 700mg medicine of about 0.1-every day, single dose or 2-4 broken dose.Perennial, definite dosage is determined by curing mainly drug effect, patient's age, body weight, disease and the reaction of clinician according to all chemical compounds.

The compounds of this invention can be with the antirheumatic of aforesaid alleviation disease, H1 antagonist, effectively treat the chemical compound of multiple sclerosis and/or effectively treat psoriatic chemical compound and unite use.The medication of these medicines and dosage can product information table with reference to the approved medicine among the Physicians DeskReference (PDR) in listed scheme and therapeutic scheme well known in the art.

In this area those of skill in the art should be appreciated that with the administration of other active medicine of The compounds of this invention use in conjunction can be according to the disease of being treated and described medicine to the drug effect of this disease and different.Equally, according to skilled clinician's knowledge, consider to medicine to patient's curative effect and consider the reaction of disease to giving medicine, can adopt different therapeutic scheme (as dosage and time).

Embodiment

The following examples example preparation of some chemical compounds of the present invention, but should not be interpreted as restriction disclosed by the invention.Those of skill in the art can understand alternative mechanism pathway and similar structures in this area.

Abbreviation below in program and scheme, having used: (aq.) of water, anhydrous (anhyd), normal-butyl (n-Bu), n-BuLi (n-BuLi), spissated (conc.), my god (d), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI), dimethyl formamide (DMF), ethanol (EtOH), ethyl (Et), ethyl acetate (EtOAc), hour (h), leaving group (LG), hydroxybenzotriazole (HOBT), metachloroperbenzoic acid (MCPBA), diisopropylamine lithium (LDA), mesyl chloride (MsCl), methanol (MeOH), minute (min), methyl (Me), lithium methide (MeLi), mole (mole/L, M), N-chloro-succinimide (NCS), N, N-dimethyl aminopyridine (DMAP), equivalent (N), pound/square inch (psi), preparation thin layer chromatography (PTLC), room temperature (rt), saturated nacl aqueous solution (saline), silica gel chromatography (sgc), 2-(tert-butoxycarbonyl oxygen base imino group)-2-phenylacetonitrile (BOC-ON), tert-butoxycarbonyl (BOC), trifluoroacetic anhydride (TFAA), trifluoroacetic acid (TFA), trifluoromethanesulfanhydride anhydride (TF ₂O), 2,2,2-trichlorine ethyl carbamate (Troc) and oxolane (THF).In typical post processor, reactant mixture is with suitable solvent such as EtOAc, Et ₂O or CH ₂Cl ₂Dilution is with suitable acidity, alkalescence or neutral aqueous solution washing.Separate organic solution, with suitable desiccant such as MgSO ₄Or Na ₂SO ₄Drying is filtered, and evaporation removes and desolvates.

General scheme 1

Can preparing wherein by the universal method shown in the following general scheme 1, A partly has A1 structure, L ²Part is-S (O ₂)-, L ¹Part is-S (O ₂)-,-C (O)-or-CH ₂-, and B partly has the formula I chemical compound of B1, B2 or B3 structure.

General scheme 1

A＝A1；L ²＝SO ₂；L ¹＝SO ₂、CO、CH ₂；B＝B1、B2、B3

The description of general scheme 1

In step 1A, 1B and 1C, the cyclic amine of formula ii, iii and iv is reacted in organic solvent such as dichloromethane or dichloroethanes with suitable alkali such as triethylamine or diisopropyl ethyl amine respectively.The aryl sulfonyl chloride that adds formula I then obtains corresponding sulfonamide v, vi and vii.This reaction can be carried out at low temperatures, as-150 ℃-0 ℃.

In step 2A, 2B and 2C, the chemical compound of formula v, vi and vii is dissolved among suitable solvent such as THF or the DME, then with itself and suitable alkali such as n-BuLi at low temperature as-110 ℃-78 ℃ reactions down.The gained anion can (as provide wherein L with suitable electrophilic reagent such as alkyl chloride ¹For-CH ₂-product), acyl chlorides (as provides wherein L ¹For-C (O)-product), aldehyde (as provides wherein L ¹For-CH ₂-product), sulfuryl fluoride (as provides wherein L ¹For-S (O ₂)-product) or disulphide (as provide wherein L ¹For-S (O ₂)-product) handle, obtain product viii, ix and x.

Can be suitable to L by selecting ³Cyclic amine with formula ii, the iii of required degree of functionality or iv is with the required L of functional group ³Import in the product.Those of skill in the art are readily understood that the method for these cyclic amine of preparation in this area.Perhaps can adopt well-known deprotection procedure by with different, required-L ³R ⁶Part is replaced among viii, ix or the x-L ³R ⁶Part obtains required-L ³R ⁶Part.

General scheme 1A

Perhaps, the method among available other method such as the following general scheme 1A prepares chemical compound viii, ix and x:

General scheme 1A

A＝A1；L ²＝-S(O ₂)-；L ¹＝-S(O ₂)-、-C(O)-、-CH ₂-；B＝B1、B2、

The formula I chemical compound of B3

The description of general scheme 1A

In step 1, with nitro compound xi Reducing agent such as SnCl ₂Or Zn, in the alcohols solvent that comprises acid (as HCl), reduce, form amino-compound xii.In step 2, described amino-compound xii can be dissolved in the acid blend (as 1: 1 mixture of acetic acid and HCl), then cooling (as to 0 ℃).Can in refrigerative solution, slowly add NaNO then ₂Aqueous solution.With gained solution stirring 0-5-1h, pour into then and refrigeratively in the presence of CuCl, use SO ₂In the saturated acetic acid solution of gas, obtain sulfonic acid chloride xiii.

In step 3A, 3B and 3C, the amine of formula ii, iii and iv is reacted in organic solvent such as dichloromethane or dichloroethanes with alkali such as triethylamine or diisopropyl ethyl amine respectively.Add then formula xiii aryl sulfonyl chloride (as, under-15 ℃-0 ℃ temperature), obtain corresponding sulfonamide viii, ix and x.

Can pass through at L ¹The preparation of suitable nitro compound xi with required degree of functionality is with the required L of functional group ¹Import in the product.Those of skill in the art are readily understood that the method for this nitro compound of preparation in this area.

Can be by being chosen in L ³Cyclic amine with suitable formula ii, the iii of required degree of functionality or iv is with the required L of functional group ³Import in the product.Those of skill in the art are readily understood that the method for this cyclic amine of preparation in this area.Perhaps, can adopt well-known deprotection procedure by with different, required-L ³R ⁶Part is replaced among viii, ix or the x-L ³R ⁶Part obtains required-L ³R ⁶Part.

General scheme 2

Wherein A have A2 or A4 (wherein Q for=CH-or=N-) structure, L ¹Part is-S (O ₂)-,-C (O)-or-CH ₂-, L ²Part is-SO ₂-, and B has the formula I chemical compound of B1, B2 or B3 structure, can prepare by the universal method system shown in the following general scheme 2.

General scheme 2

For A=A2, A4; Q is=CH-or=N-; L ²=-S (O ₂)-; L ¹=-S (O ₂)-,-C (O)-,-CH ₂-; The formula I chemical compound of B=B1, B2, B3

The description of general scheme 2

In step 1, (Boc) 2O is dissolved in suitable atent solvent such as THF, dichloromethane or the dichloromethane (dichloromethane), obtain chemical compound xv with the reaction of the chemical compound of formula xiv.

In step 2, chemical compound xv is dissolved among solvent such as THF or the DME, then with alkali such as n-BuLi (as, at-110 ℃--under 78 ℃ the reaction temperature) reaction.With gained anion SO ₂Gas treatment 1-2h rises to room temperature then.Remove and desolvate, residue is dissolved in solvent such as dichloromethane or the dichloroethanes again, handle with N-chloro-succinimide then, obtain sulfonic acid chloride xvi.

In step 3A, 3B and 3C, the amine of formula ii, iii and iv is reacted in organic solvent such as dichloromethane or dichloroethanes with alkali such as triethylamine or diisopropyl ethyl amine respectively.Add then sulfonic acid chloride xvi (as, under-15 ℃-0 ℃ reaction temperature), obtain sulfonamide xvii, xviii and the xix of the protection of corresponding N-Boc.

In step 4A, 4B and 4C, sulfonamide xvii, xviii and xix that N-Boc is protected are dissolved among solvent such as dioxane or the THF, handle with alkali such as LiOH then, obtain corresponding deprotection derivant xx, xxi and xxii respectively.

At step 5A, 5B and 5C, chemical compound xx, xxi and xxii are dissolved among solvent such as DMF or the DMSO, use alkali such as CsCO then continuously ₃Handle, then with suitable electrophilic reagent such as alkyl or aryl sulfonic acid chloride (as, wherein L is provided ¹For-S (O ₂)-product), the alkyl or aryl acyl chlorides (as, wherein L is provided ¹For-C (O)-product) or alkyl halide (as, wherein L is provided ¹For-CH ₂-product) reaction, obtain product xxiii, xxiv and XXV.

General scheme 2A

Perhaps, chemical compound xxiii, xxiv and xxv can be by other method preparations, as preparing according to following general scheme 2A.

General scheme 2A

For A=A2, A4; Q is=CH-or=N-; L ²=-S (O ₂)-; L ¹=-S (O ₂)-,-C (O)-,-CH ₂-; The formula I chemical compound of B=B1, B2, B3 (selecting route fully)

The description of general scheme 2A

In step 1; derivant xiv is dissolved in solvent such as toluene, benzene or the dimethylbenzene with indole (or azaindole), uses phase transfer catalyst such as the Aliquat_ (being methyl three caprylyl ammonium chloride) or the benzyl triethyl ammonium bromide processing of alkali such as NaOH or KOH aqueous solution and catalytic amount then.Then with gained solution with suitable by formula R ¹L ¹The electrophilic reagent that-LG represents is handled, and wherein LG represents leaving group such as chloride, bromide, fluoride or methanesulfonates, obtains chemical compound xxvi.By being selected from suitable electrophilic reagent, can import required L ¹(as ,-S (O ₂)-,-C (O)-,-CH ₂-etc.) group.

In step 2, chemical compound xxvi is dissolved among solvent such as THF or the DME, then with alkali such as n-BuLi (as, at-110 ℃--under 78 ℃ the reaction temperature) reaction.Then with gained anion SO ₂Gas treatment 1-2h rises to room temperature.Remove and desolvate, residue is dissolved in solvent such as dichloromethane or the dichloroethanes again, handle with N-chloro-succinimide then, obtain sulfonic acid chloride xxvii.

In step 3A, 3B and 3C, the amine of formula ii, iii and iv is mixed in organic solvent such as dichloromethane or dichloroethanes with alkali such as triethylamine or diisopropyl ethyl amine respectively.Add sulfonic acid chloride xxvii then, obtain corresponding sulfonamide xxiii, xxiv and xxv (as, under-15 ℃-0 ℃ reaction temperature).

General scheme 3

Wherein A partly have A3 or A5 (wherein Q for=CH-or=N-) structure, L ¹For-S (O ₂)-,-C (O)-or-CH ₂-, L ²Part is-SO ₂-and the formula I chemical compound that B partly has B1, B2 or a B3 structure can prepare by the universal method shown in the following general scheme 3.

General scheme 3

For A=A3, A5; Q is=CH-or=N-; L ²=-S (O ₂)-; L ¹=-S (O ₂)-,-C (O)-,-CH ₂-; The formula I chemical compound of B=B1, B2, B3

The description of general scheme 3

In step 1, derivant xiv is dissolved among solvent such as the DMF with indole (or azaindole), with alkali such as NaH, KH or CaH ₂Handle.Then with gained solution with suitable by formula R ¹-L ¹Electrophilic reagent that-LG represents is handled, and wherein LG represents leaving group such as chloride, bromide or mercaptan ester, obtain xxviii (as, under-15 ℃-0 ℃ temperature).By selecting suitable electrophilic reagent, can import required L ¹(as ,-S (O ₂)-,-C (O)-,-CH ₂-etc.) group.

In step 2, chemical compound xxviii is dissolved in solvent such as DMF or the toluene, use alkali such as NaH, KH or CaH then ₂Handle.Gained solution is used by formula R ⁷-LG represents, and suitable electrophilic reagent is handled, and wherein LG represents leaving group such as chloride, bromide or methanesulfonates, obtain chemical compound xxix (as, under-15 ℃-0 ℃ temperature).

In step 3, chemical compound xxix is dissolved among solvent such as THF or the DME, then with alkali such as n-BuLi (as, at-110 ℃--under 78 ℃ of reaction temperatures) reaction.With gained anion SO ₂Gas treatment 1-2h rises to room temperature then.Remove and desolvate, residue is dissolved in solvent such as dichloromethane or the dichloroethanes again, handle with N-chloro-succinimide then, obtain sulfonic acid chloride XXX.

In step 4A, 4B and 4C, the amine of formula ii, iii and iv is reacted in organic solvent such as dichloromethane or dichloroethanes with alkali such as triethylamine or diisopropyl ethyl amine respectively.Add sulfonic acid chloride xxx then, obtain corresponding sulfonamide xxxi, xxxii and xxxiii (as, under-15 ℃-0 ℃ reaction temperature).

It should be noted that in course of reaction available GPF (General Protection False radical protection does not relate to the reactive group of any process disclosed herein, reaction back available standards program is removed blocking group.Following Table II has shown some typical blocking groups:

Table II

The preparation of initiation material A

Step 1: (104.5g, (49.79g is in toluene 0.25mol) (625mL) solution 0.31mmol) to join the N-Boc-piperidines with (triphenylphosphinyl) methyl acetate (methyl (triphenylphosphoanylidene) acetate).With gained reactant mixture reflux 17h.Then reactant mixture is chilled to room temperature, vacuum concentration.Then with gained residue preadsorption on silica gel, then with its on silicagel column with 50% ethyl acetate/hexane eluting purification, (62.16 g 0.243mol), are white solid to obtain beta-unsaturated esters (a).

Step 2: (450g, 0.41mol) (90.0g is in DMSO 0.41mol) (700mL) solution for disposable adding Trimethylsulfoxonium Iodide with uncle's fourth oxygen potassium.The gained mixture at room temperature stirs 3h.With in the step 1 preparation beta-unsaturated esters (a) (59.64g 0.23mol) is dissolved among the DMSO (0.26L), and joins in the reactant mixture.Reactant mixture is at room temperature stirred 20h, join then in the saline (1L).In reactant mixture, add saturated NH then ₄The Cl aqueous solution is to regulate pH to about 7.Then with the ether extraction several times with reactant mixture, the combined ether extract, anhydrous MgSO is used in water and salt water washing ₄Drying is filtered, vacuum concentration, and (53.5g 0.20mol), is grease to obtain ester (b).

Step 3: (2N, (53.5g is in THF 0.20mol) (200mL) solution 200mL) to join the ester (b) of step 2 shape preparation with the LiOH aqueous solution.Then mixture is being stirred 17h in room temperature, water (750mL) dilution is washed with ether.Discard the ether phase, with 6N HCl with aqueous phase as acidified to pH3-4.Then with the ether extraction several times with acidifying water.The combined ether washing liquid, anhydrous MgSO is used in water and salt water washing ₄Drying is filtered, vacuum concentration, and (49.25g 0.19mol), is white solid to obtain carboxylic acid (c).

Step 4: (8.7g, 0.086mol), (9.4g, (20.0g is in acetone 0.078mol) (78mL) solution 0.86mol) to join carboxylic acid (c) with ethyl chloroformate then with triethylamine under 0 ℃.The gained mixture stirred 40 minutes down at 0 ℃.In mixture, add sodium azide (10.2g, water 0.15mol) (50mL) solution then.Then mixture is risen to room temperature, stir 4h.Add entry then, then with mixture CH ₂Cl ₂Extraction several times.Merge organic facies, water and salt water washing, dry then (anhydrous MgSO ₄), filtering, vacuum concentration obtains grease.This grease is inserted in the toluene (200mL), and (14.0g 0.094mol), stirs 17h with mixture heated to backflow and under refluxing to add trichloro-ethyl alcohol.Then reactant mixture is chilled to room temperature, adds EtOAc (250mL).Then, with mixture water and salt water washing, dry (anhydrous MgSO ₄), filter vacuum concentration.The gained residue is with silica gel chromatography purification (35% ethyl acetate/hexane), obtain carbamate (d) (24.4g, 0.061mol).

Step 5: with HCl/Et ₂(2N 50mL) joins carbamate (d) (24.4g, CH 0.061mol) for preparing in the step 4 to O ₂Cl ₂(100mL) in the solution.Reactant mixture stirred spend the night, vacuum concentration obtains (e) then, for the hygroscopicity foam (17.4g, 0.0.052mol).

The preparation of initiation material B

With known method (be Brighty, K.E; Castaldi, M.J Synlett, 1996,1097, by reference its integral body is attached to herein) initial alcohol (e) (1 α, 5 α, 6 α)-3-benzyl-6-hydroxymethyl-3-azabicyclic [3.1.0] hexane of preparation.

Step 1: with alcohol (e) (11g, 54mmol) and triethylamine (38mL 27mmol) is dissolved in CH ₂Cl ₂(200mL), and be chilled to 0 ℃.Stir refrigerative solution, drip CH ₃SO ₂Cl (its CH ₂Cl ₂Solution; 6mL, 78mmol, 25mL CH ₂Cl ₂), continue to stir 3-4h.Then with reactant mixture 100mL water washing twice, reuse 100mL saline washed twice.Separate organic facies and water, dry organic layer concentrates, and obtains crude product.With crude product with the silica gel chromatography purification (with 1: 6 ethyl acetate: the hexane eluting).Collect suitable flow point from chromatographic column, concentrate, obtaining pure chlorinated compound (f) is grease (7g, 59%).

Step 2: the chlorinated compound of preparation in the step 1 is dissolved among the DMF (100mL), uses NaN ₃(10.3g 157mmol) handles, with mixture vigorous stirring 36-48h.Then reactant mixture is diluted with 100mL water, with ethyl acetate (using twice of 100mL ethyl acetate extraction) extraction.Merge organic facies, drying concentrates, and obtains pure triazo-compound (g) (6.2g, 87%).

Step 3: with in the step 2 preparation triazo-compound (g) (6.2g, 27mmol) and triphenylphosphine (15g 57mmol) is dissolved among the 100mL THF, add then entry (6mL, 333mmol).With gained mixture vigorous stirring 16-24h.Remove and desolvate, obtain crude product amine (h), need not be further purified.

Step 4: with the crude product amine (h) and the N of preparation in the step 3, (0.66g 5.4mmol) is dissolved in CH to N-dimethyl aminopyridine (DMAP) ₂Cl ₂(IOOmL) in.Add di-tert-butyl dicarbonic acid ester (di-tertbutyl dicarbonate) in this solution (7g 33mmol), stirs 16h with reactant mixture in batches.With reactant mixture water (50mL) washed twice, reuse saline (50mL) washs once then.Separate organic layer, drying, removal of solvent under reduced pressure.Crude product is handled with silica gel chromatography, and with 1: 3 ethyl acetate: hexane was as eluant.Merge the eluting flow point, concentrate, obtain the pure carbamate of 6.9g (i) (84%).

Step 5: with the carbamate (i) of step 4 ester preparation (1.9g, 6.3mmol) be dissolved in methanol (100mL) and with palladium dydroxide (20%, 0.4g) mix.Mixture is transferred in the Parr bottle, and charging into hydrogen to pressure then is 20psi.With Parr bottle jolting 10h.Under vacuum, from the Parr bottle, remove remaining hydrogen, by Celite (kieselguhr) filtering reaction thing.Concentrated filtrate obtains pure amine B (1.4g) then.

The preparation of initiation material C

With known procedure (referring to, as Montzka, T.A.; Matiskella, J.D.; Partyka, R.A.Tetrahedron Letters 1974,14,1325; Lowe, J.A.; Drozda, S.E.; McLean, S.; Bryce, D.K.; Crawford, R.T.; Snider, R.M.; Tsuchiya, M.J.Med.Chem.1994,37,2831; The both is attached to herein with its integral body by reference) preparation N-benzyl tropane formonitrile HCN (N-benzyltropinanecarbonitrile) is (j).

Step 1: with LiAlH ₄Join among the anhydrous THF (40mL), mixture is chilled to 0 ℃ then.In mixture, drip nitrile (j) (0.9g, 3.8mmol, the solution of 10mL THF) then.Reactant mixture is risen to room temperature, stir 48h, and then be chilled to 0 ℃, add 1mL water successively, 2mL 0.5 NnaOH aqueous solution closes 1mL water quencher reaction.With gained mixture vigorous stirring 2h, pass through diatomite filtration then.Concentrated filtrate obtains pure (k), is grease (0.9g, 100%).

Step 2: with in the step 1 preparation crude product (k) and triethylamine (TEA) (0.6mL 4.3mmol) is dissolved in CH ₂Cl ₂(50mL).Add di-tert-butyl dicarbonic acid ester in this solution (0.85g 3.9mmol), stirs 16h with reactant mixture in batches.With reactant mixture 50mL water washing twice, the water washing of reuse 50mL salt once then.Dry organic facies, removal of solvent under reduced pressure.Crude product is handled with silica gel chromatography, with the CH of the saturated methanol of 2.5% ammonia ₂Cl ₂Solution is as eluant.Merge the eluting flow point, concentrate, obtain the pure carbamate ester products of 0.78g (I) (61%).

Step 3: with in the step 2 preparation carbamate (I) (0.8g 2.3mmol) is dissolved in the methanol (60mL), and with palladium dydroxide (20%, 0.08g) processing.This mixture is transferred in the Parr bottle, and then it being charged into hydrogen to pressure is 20psi.With Parr bottle jolting 10h.Under vacuum, from the Parr bottle, remove hydrogen then, reactant mixture is passed through diatomite filtration.Concentrated filtrate obtains pure amine C (0.6g then; R ²Be H).

Step 4: (0.6g, anhydrous THF (50mL) solution 2.6mmol) is chilled to-70 ℃, and handles with diisopropylamine lithium (LDA) (2.65mL, the solution of 2M THF) with initiation material N-benzyl tropane formonitrile HCN (j).(1.2g 7.8mmol) handles, and stirs 3h with ethyl iodide with gained solution then.Water quencher reaction rises to room temperature, with ethyl acetate (100mL) dilution.Separate organic layer, use the 50mL water washing successively once, with 50mL saline washed twice.Dry organic facies concentrates, gained crude product silica gel chromatography purification, and with 1: 3 ethyl acetate: hexane was as the eluant mixture.With being similar to the method for describing in the step 1,2 and 3 chemical compound (m) is converted into chemical compound (c) (R ²=C ₂H ₅), except using wherein R ²Be C ₂H ₅Similar initiation material to replace N-benzyl tropane formonitrile HCN (j) (be R ²=H).

Embodiment 1

The chemical compound of the general formula shown in above having can be by following method or the similar method preparation of understanding by those of skill in the art in this area.

Step 1: (1.45g 14.4mmol) joins carbamate A (1.94g, the CH of 5.75mmol with TEA under 0 ℃ ₂Cl ₂In the solution, and disposable then adding 4-chlorobenzene sulfonyl chloride (1.52g, 7.18mmol).Reactant mixture is risen to stirring at room 2h, with the dichloromethane dilution, with 1N HCl, water and salt water washing, dry then (anhydrous MgSO ₄), filter vacuum concentration.Crude product silica gel chromatography purification, obtain sulfonamide (la) (2.0g, 4.2mmol).

Step 2: (17.7g, (2.0g is 4.2mmol) and in the solution of AcOH (42mL) 273mmol) to join sulfonamide (1a) with zinc powder.The gained mixture is stirring 3h in room temperature, with the EtOAc dilution, uses filtered through silica gel, the filtrate vacuum concentration.The gained residue is dissolved in dichloromethane, adds saturated NaHCO then ₃Solution was with mixture vigorous stirring 15 minutes.With the water layer dichloromethane extraction.Merge organic facies, water and salt water washing, dry (anhydrous MgSO ₄), filter, vacuum concentration, obtain amine (1b) (0.95g, 3.2mmol).

Step 3: (0.37g, (0.26g is in dichloroethanes 0.86mmol) (3mL) solution 2.6mmol) to join amine (1b) with Trifluoroacetic Acid Ethyl Ester.The gained mixture is warming up to 45 ℃, and the adding Trifluoroacetic Acid Ethyl Ester (0.24g, 1.72mmol).Reactant mixture is warming up to 60 ℃ then, stirs 6h, vacuum concentration then.Spissated crude product is with silica gel chromatography purification (30%EtOAc/ hexane), obtain trifluoroacetamide (1c) (0.167g, 0.42mmol).

Step 4: (1.6M, (0.16g is in THF solution 0.42mmol) 0.59mL) to join trifluoroacetamide (1c) with n-BuLi under-78 ℃.Reactant mixture is stirred 0.5h, add 2-fluorophenyl disulphide (0.16g, THF 0.63mmol) (0.6mL) solution then.The gained mixture is stirred 2h down at-78 ℃.Add entry then, mixture is risen to room temperature, extract with EtOAc.Merge organic facies, water and salt water washing, dry (anhydrous MgSO ₄), filter vacuum concentration.Spissated product is with silica gel chromatography purification (35%EtOAc/ hexane), obtain the racemic intermediate product (0.13g, 0.25mmol).This is not further purified or isolating racemic intermediate product is dissolved among the DCE, add m-CPBA (0.21g, 0.84mmol).The gained reactant mixture is at room temperature stirred 17h, use CH ₂Cl ₂Dilution, water and salt water washing, dry (anhydrous MgSO ₄), filter vacuum concentration.The gained enriched product is with silica gel preparative thin layer chromatography method purification (45%EtOAc/ hexane), obtain (1d) (0.067g, 0.12mmol).

Step 5: with chirality HPLC (Chiralpak AD post, 5cm * 50cm, 20 μ m particle diameters, flow velocity is 48mL/min) separation two enantiomer amine (1b) (1.42g, 4.71mmol) usefulness 25%IPA/ hexane eluting, obtain isomer A (1e) (0.57g, 1.9mmol) and isomer B (1f) (0.55g, 1.8mmol).

Step 6: (0.16g, 1.58mmol), (0.20g, (0.24g is in DCE 0.79mmol) (2.6mL) solution 0.94mmol) to join enantiomer (1e) with trifluoroacetic anhydride then with TEA under 0 ℃.Reactant mixture is risen to room temperature, stir 18h.Then with mixture CH ₂Cl ₂Dilution, water and salt water washing, dry (anhydrous MgSO ₄), filter vacuum concentration.Spissated product is with silica gel chromatography purification (30%EtOAc/ hexane), obtain trifluoroacetamide (1g) (0.25g, 0.63mmol).

Step 7: (1.8M, (0.21g is in THF 0.54mmol) (2mL) solution 0.67mL) to join the trifluoroacetamide (1g) that is chilled to-78 ℃ with n-BuLi.Reactant mixture was stirred 30 minutes, add 2-fluorophenyl disulphide (0.17g, THF 0.68mmol) (0.8mL) solution then.Reactant mixture is slowly risen to room temperature through 17h.Add saturated NH then ₄Cl solution extracts reactant mixture with EtOAc.Merge organic facies, water and salt water washing, dry (anhydrous MgSO ₄), filter vacuum concentration.Products therefrom with silica gel chromatography purification (30%EtOAc/ hexane), is obtained initial trifluoroacetamide and required thioether mixture of products (0.13g).This mixture that will not be further purified is inserted among the DCE (2mL), and adding m-CPBA (0.22g, 0.90mmol).The gained mixture at room temperature stirs 22h.Then with reactant mixture CH ₂Cl ₂Dilution, water and salt water washing, dry (anhydrous MgSO ₄), filter vacuum concentration. spissated product is with silica gel chromatography purification (30-40%EtOAc/ hexane), obtain (1h) (0.034g, 0.061mmol).

Step 8: (2N, (0.034g is in THF 0.06mmol) (0.5mL) solution 0.09mL) to join (1h) with the LiOH aqueous solution.The gained mixture is at room temperature stirred 27h, add entry then, mixture is extracted with EtOAc.Merge organic facies, water and salt water washing, dry (anhydrous MgSO ₄), filter, vacuum concentration, obtain amine (1i) (0.028g, 0.06mmol).

Step 9: (0.012g, 0.12mmol), then (0.010g, (0.026g is in DCE 0.06mmol) (0.4mL) solution 0.09mmol) to join amine (1i) with mesyl chloride with TEA.The gained reactant mixture is at room temperature stirred 19h, vacuum concentration then.Spissated product is with silica gel preparative thin layer chromatography method purification (70%EtOAc/ hexane), obtain Methanesulfomide chemical compound 17 (0.016g, 0.03mmol).

Step 10: remain under 0 ℃ that (0.15g, 1.5mmol), then (0.19g, (0.22g is in DCE 0.73mmol) (2.4mL) solution 0.88mmol) to join amine (1f) with trifluoroacetic anhydride with TEA.Under agitation reactant mixture is slowly risen to room temperature reaction 17h then.In reactant mixture, add CH then ₂Cl ₂, water and salt water washing, dry (anhydrous MgSO ₄), filter, vacuum concentration, obtain trifluoroacetamide (1j) (0.27g, 0.67mmol).

Step 11: remain on that (1.8M, (0.25g is in THF 0.64mmol) (2.1ml) solution 0.80mL) to join (1j) with n-BuLi under-78 ℃.Reactant mixture was stirred 25 minutes down at-78 ℃.In reactant mixture, add 2-fluorophenyl disulphide (0.24g, THF 0.96mmol) (0.8mL) solution then.Through 19h reactant mixture is slowly risen to room temperature.Add saturated NH then ₄Cl solution extracts reactant mixture with EtOAc.Merge organic facies, water and salt water washing, dry (anhydrous MgSO ₄), filter vacuum concentration.Residue is with silica gel chromatography purification (30%EtOAc/ hexane), obtain thioether (0.23g, 0.44mmol).To not be further purified or isolating this thioether is inserted among the DCE (3mL), (0.38g 1.54mmol) at room temperature stirs 24h to add m-CPBA then in mixture.In mixture, add CH then ₂Cl ₂, water and saline purging compound, dry (anhydrous MgSO ₄) organic layer, filter vacuum concentration.Residue is with silica gel chromatography purification (35%EtOAc/ hexane), obtain (1k) (0.13g, 0.23mmol).

Step 12: at room temperature (2N, (0.13g is in THF 0.23mmol) (1.5mL) solution 0.35mL) to join (1k) with the LiOH aqueous solution.Reactant mixture is stirred 21h.Add entry then, reactant mixture is extracted with EtOAc.Merge organic facies, water and salt water washing, dry (anhydrous MgSO ₄), filter, vacuum concentration, obtain amine (11) (0.11g, 0.23mmol).

Step 13: at room temperature (0.02g, 0.20mmol), then (0.016g, 0.15mmol) (0.046g is in DCE 0.10mmol) (0.7mL) solution to amine (11) mutually in adding with mesyl chloride with TEA.Reactant mixture is at room temperature stirred 17h, vacuum concentration.Residue is with silica gel preparative thin layer chromatography method purification (70%EtOAc/ hexane), obtain chemical compound 18 (0.04g, 0.08mmol).

Step 14: (0.02g 0.16mmol), follows TF with TEA under-78 ℃ ₂(0.035g 0.12mmol) joins amine (11) (0.05g, CH 0.11mmol) to O ₂Cl ₂In the solution.Reactant mixture is stirred 5h down at-78 ℃, rise to room temperature then.With CH ₂Cl ₂Join in the reactant mixture, then water and salt water washing.Dry then (anhydrous MgSO ₄) organic layer, filter vacuum concentration.Residue is with silica gel preparative thin layer chromatography method purification (35%EtOAc/ hexane), obtain chemical compound 19 (0.045g, 0.08mmol).

Chemical compound 16,23,27,28,29,30,31,32,33,34,35,36,37,38,39 and 40 (table 1) are by the similar method preparation among the embodiment 1 that describes in the above.The very molten easy understanding of those of skill in the art these changes in the method for embodiment 1 in this area.

For example, the mode that chemical compound 16 usefulness are similar to chemical compound 17 and 18 prepares, only racemic mixture (1b) is handled with step 6-9, and (be step 5) and there is not the chiral separation step.

The mode that chemical compound 23,27 and 28 usefulness are similar to chemical compound 19 prepares, and only in step 11, replaces 2-fluorophenyl disulphide with 2-pyridyl disulfide, 4-Trifluoromethoxyphen-l disulphide and 4-methoxybenzene based bisulfide respectively.

The mode that chemical compound 29 usefulness are similar to chemical compound 19 prepares, and only in step 1, A reacts with 4-trifluoromethyl benzene sulfonyl chloride.

The mode that chemical compound 30 usefulness are similar to chemical compound 19 prepares, and only in step 1, A is and the reaction of 4-trifluoromethyl benzene sulfonyl chloride, and in step 11, replaces 2-fluorophenyl disulphide with 4-Trifluoromethoxyphen-l disulphide.

The mode that chemical compound 31 usefulness are similar to chemical compound 19 prepares, and only in step 1, A is and the reaction of 4-trifluoromethyl benzene sulfonyl chloride, and in step 11, replaces 2-fluorophenyl disulphide with the 2-pyridyl disulfide.

The mode that chemical compound 32 usefulness are similar to chemical compound 19 prepares, and only in step 1, A reacts with 4-trifluoromethoxy benzene sulfonyl chloride.

The mode that chemical compound 33 usefulness are similar to chemical compound 19 prepares, and only in step 1, A is and the reaction of 4-methoxybenzene sulfonic acid chloride, and in step 11, replaces 2-fluorophenyl disulphide with the 2-pyridyl disulfide.

The mode that chemical compound 34 usefulness are similar to chemical compound 19 prepares, and only in step 1, A is and the benzene sulfonyl chloride reaction, and in step 11, replaces 2-fluorophenyl disulphide with the 2-pyridyl disulfide.

The mode that chemical compound 35 usefulness are similar to chemical compound 19 prepares, and only in step 1, A is and the reaction of 4-fluorobenzene sulfonic acid chloride, and in step 11, replaces 2-fluorophenyl disulphide with the 2-pyridyl disulfide.

The mode that chemical compound 36 usefulness are similar to chemical compound 18 prepares, and only in step 7, replaces 2-fluorophenyl disulphide with the 2-pyridyl disulfide.

The mode that chemical compound 37 usefulness are similar to chemical compound 18 prepares, and only in step 7, replaces 2-fluorophenyl disulphide with the 2-pyridyl disulfide, and in step 9, replaces mesyl chloride with the cyclopropyl sulfonic acid chloride.

The mode that chemical compound 38 usefulness are similar to chemical compound 19 prepares, and only in step 1, A is and the reaction of 4-hydroxy benzenes sulfonic acid chloride, and in step 11, replaces 2-fluorophenyl disulphide with the 2-pyridyl disulfide.

The mode that chemical compound 39 usefulness are similar to chemical compound 32 prepares, only in step 11, replace 2-fluorophenyl disulphide with the 2-pyridyl disulfide, and in step 14, the amine midbody product that generates after step 12 is and 2,2 2-trifluoroethyl triflate (2,2,2-trifluoroethyl triflate) rather than and TF ₂The O reaction.

The mode that chemical compound 40 usefulness are similar to chemical compound 19 prepares, and only at step 1 ester, A is and 4-trifluoromethoxy benzene sulfonyl chloride, and at step 11 ester, replaces 2-fluorophenyl disulphide with the 2-pyridyl disulfide.

Embodiment 2

The chemical compound of general formula shown in above having can be by method that describes below or the similar approach preparation of understanding by those skilled in the art.

Step 1: (0.62g 6.12mmol), follows (Boc) with TEA ₂(0.84g, (0.92g in DCE 3.06mmol) (10mL) solution, prepares in the step 5 of the method that it is described in embodiment 1 O 3.82mmol) to join midbody compound (1f).Reactant mixture is at room temperature stirred 16h.Then with reactant mixture CH ₂Cl ₂Dilution is with 1N NaOH, 1N HCl, water and salt water washing.Dry then (anhydrous MgSO ₄) organic layer, filter, vacuum concentration, obtain carbamate (2a) (1.22g, 3.04mmol).

Step 2: under-78 ℃ with NH ₃(125mL) condenses in flask.At this NH ₃The middle solid sodium piece that adds is to keep blue.With in the step 1 preparation carbamate (2a) (1.22g, THF 3.0mmol) (12mL) solution joins agglomerative NH ₃In the sodium mixture.Reactant mixture becomes orange, adds sodium again until keeping blue.Reactant mixture is stirred 2.5h at-78 ℃.Add NH then ₄The Cl solid, and make N ₂By reactant mixture with evaporated liquor NH ₃Add solid NaCl and 1N NaOH then, with reactant mixture CH ₂Cl ₂Extraction.The organic facies water and the salt water washing that merge, dry then (anhydrous MgSO ₄), filter, vacuum concentration, obtain non-racemic amines (2b) (0.53g, 2.34mmol).

Step 3: with 50%NaOH aqueous solution (30mL), then (0.025g, 0.11mmol) (6.0g, (3.0g is in toluene 26mmol) (20mL) solution 31mmol) to join indole with 2-fluorophenyl sulfonic acid chloride with benzyl triethyl ammonium bromide.Reactant mixture is at room temperature stirred 20h.Add entry then, reactant mixture is extracted with EtOAc.Merge organic facies, water and salt water washing, dry (anhydrous MgSO ₄), filter, vacuum concentration, obtain (2c) (7.0g, 25.7mmol).

Step 4: (1.1M, (1.32g is in THF 13.1mmol) (22mL) solution 12mL) to join diisopropylamine with n-BuLi under 0 ℃.Gained solution stirs 1h down at 0 ℃, thereby LDA (diisopropylamine lithium) is provided solution.(3.0g, in THF 10.9mmol) (26mL) solution, keeping temperature is-78 ℃ then LDA solution to be joined the indole derivatives (2c) for preparing in the step 3.The gained reactant mixture is stirred 1h down at-78 ℃, in reactant mixture, feed SO then ₂Gas 15 minutes.Remove cooling bath, make reaction rise to room temperature.With the reactant mixture vacuum concentration.The gained solid is dissolved in CH ₂Cl ₂(26mL), and the adding N-chloro-succinimide (1.75g, 13.1mmol).The gained reactant mixture was at room temperature stirred 75 minutes, use CH then ₂Cl ₂Dilution, water and salt water washing, dry (anhydrous MgSO ₄), filter vacuum concentration.The gained residue is adsorbed in silica gel, with silica gel chromatography purification (15%EtOAc/ hexane), obtain comprising about 20% initial indole (2c) (2d) (1.3g, 3.5mmol).

Step 5: (0.059mL, 0.42mmol), (0.04g 0.17mmol) joins amine (2b) (0.10g, CH 0.21mmol) to follow the indole sulfonic acid chloride (2d) that will prepare in the step 4 with TEA ₂Cl ₂(1.5mL) in the solution.The gained reactant mixture at room temperature stirs 20h.Reactant mixture is diluted with EtOAc, with 1N HCl, water and salt water washing.Dry organic facies (anhydrous MgSO ₄), filter, vacuum concentration obtains grease, with it with silica gel preparative thin layer chromatography method purification (40%EtOAc/ hexane), obtain (2e) (0.07g, 0.12mmol).

Step 6: (4N 1.5mL) joins N-boc amine (2e) (0.07g, CH 0.12mmol) for preparing in the step 5 with the HCl/ dioxane ₂Cl ₂In the solution.Reactant mixture is at room temperature stirred 17h, and vacuum concentration obtains (2f) quantitatively output then.Residue is inserted CH ₂Cl ₂In, adding TEA (0.043mL, 0.31mmol).To react mixing and be chilled to-78 ℃, add TF then ₂O (0.022mL, 0.13mmol).Through 15h reactant mixture is slowly risen to room temperature, then with the EtOAc dilution, with 1N HCl, water and salt water washing.Separate organic layer, dry (anhydrous MgSO ₄), filter vacuum concentration.Residue is with silica gel preparative thin layer chromatography method purification (35%EtOAc/ hexane), obtain chemical compound 22 (0.05g, 0.08mmol).

The raceme of employing amine (1a) or the isomer of fractionation (as, by the racemic mixture (1b) of the method for embodiment 1 preparation or the isomer (1e) that splits or (1f)), the method that the chemical compound 20,21,24,25,26,41,42 of table 1 and 43 usefulness are similar among the above-described embodiment 2 prepares.Those of skill in the art understood during these changes in the method for embodiment 2 were easy to by this area.

The mode that chemical compound 20 usefulness are similar to chemical compound 22 prepares, and what only use in step 1 is racemic amines (1b) rather than isomer (1f), and in step 6, replaces TF with mesyl chloride ₂O.

The mode that chemical compound 21 usefulness are similar to chemical compound 22 prepares, and what only use in step 1 is racemic amines (1b) rather than isomer (1f).

The mode that chemical compound 25 usefulness are similar to chemical compound 22 prepares, and what only use in step 5 is racemic amines (A) rather than isomer (2b), and in step 3, replaces indole with the 5-bromo indole.

The mode that chemical compound 24 usefulness are similar to chemical compound 25 prepares, and only uses amine (A) to replace amine (2b), and in step 5, replaces TF with mesyl chloride ₂O.

The mode that chemical compound 26 usefulness are similar to chemical compound 25 prepares, and only uses amine isomer (1f) to replace racemic amines (A).

The mode that chemical compound 41 usefulness are similar to chemical compound 22 prepares, and only replaces 2-fluorophenyl sulfonic acid chloride with 2-pyridine radicals sulfonic acid chloride in step 3.

The mode that chemical compound 42 usefulness are similar to chemical compound 21 prepares, and only uses azaindole in step 3

Replace indole.

The mode that chemical compound 43 usefulness are similar to chemical compound 42 prepares, and only in step 6, replaces TF with mesyl chloride ₂O.

Embodiment 3

Chemical compound with the general formula that shows above can be with method shown in following or the similar method preparation of understanding with those of skill in the art in this area.

Step 1: (0.7g, anhydrous THF (30mL) solution 5.5mmol) is chilled to 0 ℃, with NaH (0.26g, 11.1mmol) processing with 2-fluorobenzene mercaptan.After stirring 0.5h, add 2-fluoro-4-chloronitrobenzene, reactant mixture is risen to room temperature.Behind the restir 4h, reactant mixture is diluted with ethyl acetate (50mL), water (50mL) is used saline (50mL) washing then successively.Separate organic facies, dry concentrating obtains 1.5g nitro compound (3a), and it is used for following step without being further purified.

Step 2: stannic chloride (2.4g) is dissolved among 3: 1 ethanol: the HCl (30mL), is chilled to 0 ℃, stir until dissolving.Add the nitro compound (3a) that obtains in the step 1 (1.2g, 3.9mmol), the gained suspension at room temperature stirs 10h in batches.With NaOH aqueous solution (10mL, 1N) neutralization reactant.Volatile ingredient (as, ethanol) is removed in decompression, with ethyl acetate (twice of 50mL ethyl acetate extraction) product is extracted from aqueous phase.Merge organic facies, dry (anhydrous MgSO ₄).Remove and desolvate, obtain 1.03g amine (3b), it is used for following step without being further purified.

Step 3: (10.3g 3.6mmol) is dissolved in 3: 2 acetic acid: HCl (10mL), and is chilled to 0 ℃ will to derive from the amine (3b) of step 2.With NaNO ₂(0.3g, aqueous solution 4.3mmol) are added drop-wise in this solution, stir 0.5h.Gained diazol intermediate mixture slowly poured into use SO ₂In the pre-saturated acetic acid of gas, use the CuCl (0.8g) of catalytic amount to handle then.Mixture is stirred 1h, be poured on the trash ice then.With this mixture 50mL CH ₂Cl ₂Extracting twice, drying concentrates, and obtains being used for the sulfonic acid chloride (3c) of next step.

Step 4: with amine B (0.06g, 0.283mmol) and triethylamine (0.3mL, dichloromethane 1.4mmol) (25mL) solution is handled with the sulfonic acid chloride (3c) of preparation in the step 3.The gained mixture at room temperature stirs 5h.Reactant mixture with dichloromethane (50mL) dilution, is used NaHCO successively ₃Aqueous solution (50mL), water (two parts, every part of 50mL) and saline (50mL) washing.Separate organic facies, drying concentrates, and obtains crude product (3d), and with preparing thin layer silica gel chromatography purification, 1: 2 ethyl acetate: hexane is as eluant with it.

Step 5: product (3d) (0.088g, CH 0.172mmol) that will derive from step 4 ₂Cl ₂(50mL) (0.097g 0.4mmol) handles solution, and the gained mixture stirs 72h with m-CPBA.With reactant mixture CH ₂Cl ₂(50mL) 5%NaHSO is used in dilution successively ₃Aqueous solution (50mL), NaHCO ₃Aqueous solution (50mL), water (50mL) and saline (50mL) washing.Separate organic facies, dry (Na ₂SO ₄), filter, concentrate.The gained crude product is with preparing thin layer silica gel chromatography purification, and use ethyl acetate: hexane (1: 2) obtains the pure sulfone product of 0.085g (3e) as solvent.

Step 6: with sulfone product (3e) (0.085g, CH 0.156mmol) of preparation in the step 5 ₂Cl ₂(10mL) (0.06mL 0.77mmol) handles solution, stirs 2h with trifluoroacetic acid.With reactant mixture NaHCO ₃CH is used in the aqueous solution neutralization ₂Cl ₂(50mL) dilution, water (50mL) and saline (30mL) washing successively.Separate organic facies, dry (Na ₂SO ₄), concentrate, obtain pure amine (3f) (0.08g).

Step 7: with the amine (3f) for preparing in the preceding step (0.03g, 0.067mmol) and triethylamine (0.009mL, CH 0.0667mmol) ₂Cl ₂(10mL) solution is chilled to-70 ℃, and (0.016g 0.059mmol) handles with trifluoromethanesulfanhydride anhydride.Reactant mixture is stirred 1h, use NaHCO then ₃(20mL) aqueous solution quencher.Mixture with quencher rises to room temperature then, uses CH ₂Cl ₂(50mL) dilution.Separate organic facies, drying concentrates, and then crude product is handled with the silica gel preparative thin layer chromatography method, and with 1: 2 ethyl acetate: hexane obtained pure compound 11 (0.02g) as solvent.

Chemical compound 6,7,8,9,56 in the table 1 and 57 usefulness are similar to the method preparation among the above-described embodiment 3.Change in the method for these embodiment 3 is easy to be understood by those of skill in the art in this area.

The mode that chemical compound 6 usefulness are similar to chemical compound 11 prepares, and only in step 1, replaces 2-fluorobenzene mercaptan with 2-pyridine mercaptan.

The mode that chemical compound 7 usefulness are similar to chemical compound 6 prepares, and only in step 7, replaces trifluoromethanesulfanhydride anhydride with mesyl chloride.

The mode that chemical compound 8 usefulness are similar to chemical compound 6 prepares, and only in step 1, replaces 2-fluoro-4-chloronitrobenzene with 2-fluoro-4-trifluoromethoxy Nitrobenzol.

The mode that chemical compound 9 usefulness are similar to chemical compound 11 prepares, and only in step 7, replaces trifluoromethanesulfanhydride anhydride with mesyl chloride.

The mode that chemical compound 56 usefulness are similar to chemical compound 6 prepares, and only in step 7, the amine midbody product of preparation is and 2,2 2-trifluoroethyl triflate rather than and TF in the step 6 ₂The O reaction.

Chemical compound 57 is according to general scheme 1 preparation, wherein intermediate vi (wherein s=0 and R ², R ³And R ⁴=H) react with n-BuLi, follow and (t-BuOC (O)) ₂The O reaction.Intermediate vi prepares (even amine B and TEA and the reaction of 4-chlorobenzene sulfonyl chloride) with the method that is similar to chemical compound among the embodiment 1 (1a).

Embodiment 4

The chemical compound (being chemical compound 50,51,58 and 59) of general formula shown in above having is with being similar among the embodiment 3 the program preparation of describing, and only uses amine C (R wherein ²For H or-CH ₂CH ₃) replacement amine B.Change in the method for these embodiment 3 is easy to be understood by those of skill in the art in this area.

For example, the mode that chemical compound 50 and 51 usefulness are similar to chemical compound 6 and 7 prepares, only in step 4, with amine C (R ²=H) replace amine B.Similarly, chemical compound 58 and 59 is respectively with the method preparation that is similar to chemical compound 56 and 6, only in step 4, with amine C (R ²=-CH ₂CH ₃) replacement amine B.

Chemical compound 55 is according to general scheme 1 preparation, wherein intermediate vii (s=2 wherein, Z=-CH ₂-and R ², R ³And R ⁴=H) react with n-BuLi, follow and (t-BuOC (O)) ₂The O reaction.Intermediate vii prepares (even amine C and TEA and the reaction of 4-chlorobenzene sulfonyl chloride) with the method that is similar to chemical compound among the embodiment 1 (1a).

Embodiment 5

Step 1: remain on-70 ℃, ((10.0g is in THF solution 46mmol) (150mL) 50.6mmol) to be added drop-wise to the N-Boc indole through 0.5h for 20.3mL, the hexane solution of 2.5M with n-BuLi.Mixture is stirred 1h, in solution, feed SO then ₂Gas 1h.Through 2h reactant mixture is risen to 10 ℃ then.Removal of solvent under reduced pressure, residue are dissolved in CH again ₂Cl ₂(200mL), (9.2g 69mmol) handles, and stirs 10h with NCS.With reactant mixture water successively (2 * 50mL) and saline (2 * 50mL) washing.Dry organic facies concentrates, and obtains crude product, with it by silicagel pad, with 9: 1 hexanes: ethyl acetate is as eluant.The flow point that vacuum concentration is collected obtains 19.5g indole sulfonic acid chloride (5a).

Step 2: with amine B (0.3g, 1.4mmol) and triethylamine (0.99mL, CH 7mmol) ₂Cl ₂(30mL) at room temperature (0.5g 1.55mmol) handles solution with the indole sulfonic acid chloride (5a) for preparing in the step 1.Mixture is stirred 16h, use CH then ₂Cl ₂(100mL) dilution, water (50mL) washs once, with saline (each 50mL) washed twice.Separate organic facies, dry (Na ₂SO ₄), concentrate, obtain crude product, it is used the silica gel chromatography purification, with 1: 1 ethyl acetate: hexane was as eluant.Collection also merges suitable flow point, and solvent removed in vacuo obtains pure products (5b) (0.46g).

Step 3: with the product (5b) of preparation in the step 2 (0.45g, 0.91mmol) and LiOH (7mL, 1M H ₂O solution) dioxane (25mL) solution heats 16h at 40 ℃, and then at 60 ℃ of heating 1h.Remove and desolvate, residue is dissolved in ethyl acetate (50mL) water (50mL) and saline (50mL) washing.Dry organic facies, (Na ₂SO ₄) concentrate, obtain crude product, then it is handled with the silica gel preparative thin layer chromatography method, obtain 0.36g pure products (5c).

Step 4: with product (5c) 3 (0.25g, DMF 0.64mmol) (20mL) the solution CsCO of preparation in the step 3 ₃(0.5g 1.6mmol) handles, and (0.15g 0.7mmol) handles, and stirs 40h to use 2-fluorophenyl sulfonic acid chloride then.Then reactant mixture is diluted water (50mL) and saline (50mL) washing with ethyl acetate (50mL).Dry organic facies concentrates, and obtains crude product, and it is used silica gel preparative thin layer chromatography method purification, and use ethyl acetate: hexane (1: 2) eluting obtains pure products (5d) (0.25g).

Step 5: with product (5d) (0.07g, CH 0.13mmol) of preparation in the step 4 ₂Cl ₂(50mL) (0.07g 0.636mmol) handles solution at room temperature with trifluoroacetic acid.Reactant mixture is stirred 3h, remove then and desolvate, obtain amine product (5e), it is used for following step without further purification.

Step 6: with in the step 5 preparation amine product (5e) and triethylamine (0.024mL 0.14mmol) is dissolved in CH ₂Cl ₂(15mL), be chilled to-70 ℃.(0.034g 0.042mmol), stirs 1h to add trifluoromethanesulfanhydride anhydride in this solution.Reactant mixture is risen to 0 ℃ then, use CH ₂Cl ₂(50mL) dilution, water (each 15mL) washed twice, with saline (15mL) washing once.Dry organic facies, (Na ₂SO ₄), concentrating, the gained crude product is with silica gel preparative thin layer chromatography method purification, and with 1: 2 ethyl acetate: the hexane eluting obtained 0.025g pure compound 12.

Chemical compound 3,10,13,14 in the table 1 and 15 usefulness are similar to the method preparation among the above-described embodiment 5.Change in the method for these embodiment 5 is easy to be understood by those of skill in the art in this area.

For example, the mode that chemical compound 3 usefulness are similar to chemical compound 12 prepares, and only in step 1, uses shielded azaindole

Replace the N-Boc indole.

The mode that chemical compound 10 usefulness are similar to chemical compound 12 prepares, and only in step 4, replaces 2-fluorophenyl sulfonic acid chloride with 2-pyridine radicals sulfonic acid chloride, and in step 6, replaces trifluoromethanesulfanhydride anhydride with mesyl chloride.

The mode that chemical compound 13 usefulness are similar to chemical compound 12 prepares, and only in step 6, replaces trifluoromethanesulfanhydride anhydride with mesyl chloride.

The mode that chemical compound 14 usefulness are similar to chemical compound 12 prepares, only in step 1, with shielded 5-cyanoindole

Replace the N-Boc indole, and in step 4, replace 2-fluorophenyl sulfonic acid chloride with 2-pyridine radicals sulfonic acid chloride.

The mode that chemical compound 15 usefulness are similar to chemical compound 12 prepares, and only in step 4, replaces 2-fluorophenyl sulfonic acid chloride with 2-pyridine radicals sulfonic acid chloride.

Embodiment 6

The chemical compound of general formula shown in above the tool is with being similar to the program preparation of describing among the embodiment 5, and only using amine C (is R ₂=H or-CH ₂CH ₃) replacement amine B.Change in the method for these embodiment 5 is easy to be understood by those of skill in the art in this area.For example, chemical compound 46-49 prepares with the mode that is similar to chemical compound 12,13,15,10 respectively, only uses amine C (R ²=H) replace amine B.Similarly, the mode that chemical compound 54 usefulness are similar to chemical compound 12 prepares, and only uses amine C (R ²=-CH ₂CH ₃) replacement amine B.

Embodiment 7

Step 1: (2.4g 20mmol) joins in the DMF solution (100mL) that comprises NaH (0.78g) with indole under 0 ℃.Stir this solution after 15 minutes, (5.2g 20mmol), rises to room temperature through 4h with reactant mixture to add 2-fluorophenyl disulphide.Remove and desolvate, crude product is dissolved in ethyl acetate (100mL) again, then water (50mL) and saline (50mL) washing successively.Dry organic facies concentrates.Products therefrom is from hexane: recrystallization the ethyl acetate mixture, thus obtain (7a), be white solid (3.7g).

Step 2: with (7a) (2.5g, CH 10mmol) of preparation in the step 1 ₂Cl ₂(50mL) (10.6g, 62mmol) batch processing are stirred 40h with the gained mixture to solution then with m-CPBA.With reactant mixture 100mL CH ₂Cl ₂NaHSO is used in dilution successively ₃Aqueous solution (50mL), NaHCO ₃Aqueous solution (50mL) and saline (50mL) washing.Dry organic facies concentrates, and obtains crude product, without being further purified, it is methylated with following procedure.

The crude product for preparing above is dissolved among the THF (50mL), and (0.864g 36mmol) handles, and then (3.4mL 36mmol) handles with iodomethane with NaH.Then mixture is stirred 20h, with the quencher of 5mL water, with ethyl acetate (100mL) dilution, water (50mL) and saline (50mL) washing successively.Dry organic facies concentrates, and obtains crude product (7b), with it with silica gel chromatography purification (with 3: 7 ethyl acetate: hexane was as eluant).

Step 3: (1.4g, anhydrous THF 4.8mmol) (40 mL) solution is chilled to-78 ℃, handles with diisopropylamine lithium (7mmol), stirs 40min, feeds SO then in solution with (7b) of preparation in the step 2 ₂Gas 0.5h.Reactant mixture is stirred 15h down at-78 ℃, rise to room temperature then.Decompression is reduced to 15mL with the volume of solution, adds refrigerative hexane, thereby solid is gone out from solution precipitation.Filter collecting precipitation, wash with cold hexane (50mL).This solid is dissolved in CH again ₂Cl ₂(50mL), (1.3g 9.5mmol) handles, and stirs 0.5h with N-chloro-succinimide.Then with reactant mixture water (50mL) and saline (50mL) washing, drying (Na then ₂SO ₄).Remove and desolvate, crude product is used ethyl acetate by silicagel pad: hexane (1: 2) eluting, concentrate, and obtain pure products (7c) (1.4g, 75%).

Step 4: with amine B (0.17g, 0.8mmol) and triethylamine (0.55mL, (0.28g 0.78mmol) handles dichloromethane 3.94mmol) (25mL) solution with the sulfonic acid chloride (7c) of preparation in the step 3.Reactant mixture is at room temperature stirred 10h,, use NaHCO successively with dichloromethane (50mL) dilution ₃Aqueous solution (50mL), water (two parts, every part of 50mL) and saline (50mL) washing.Dry organic facies concentrates, and obtains crude product.Crude product is with preparation thin layer silica gel chromatography purification, and with 1: 2 ethyl acetate: hexane was as eluant, thereby obtained 0.26g pure products (7d).

Step 5: with carbamate (7d) (0.25g, CH 0.44mmol) of preparation in the step 4 ₂Cl ₂(20mL) (0.2mL 2.6mmol) handles solution, stirs 4h with trifluoroacetic acid.With reactant mixture NaHCO ₃CH is used in the aqueous solution neutralization ₂Cl ₂(50mL) dilution, water (50mL) and saline (30mL) washing successively.Dry organic facies, (Na ₂SO ₄) concentrate, obtain pure amine (7e) (0.18g).

Step 6: with the amine (7e) of preparation in the step 5 (0.09g, 0.19mmol) and triethylamine (0.032mL, CH 0.23mmol) ₂Cl ₂(20mL) solution is chilled to-70 ℃, and (0.048g 0.173mmol) handles with trifluoromethanesulfanhydride anhydride.Reactant mixture is stirred 1h, use NaHCO then ₃Aqueous solution (20mL) quencher.The gained mixture rises to room temperature, uses CH ₂Cl ₂(50mL) dilution.Dry organic facies concentrates, and the gained crude product is used 5%CH with silica gel preparative thin layer chromatography method purification ₃OH/CH ₂Cl ₂As developing solvent, obtain pure compound 1 (0.06g).

Chemical compound 2,4 and 5 usefulness are similar to the method preparation of describing among the embodiment 7, and it is easy to be understood by those of skill in the art in this area.For example, chemical compound 2 only in step 6, replaces trifluoromethanesulfanhydride anhydride with mesyl chloride by being similar to the method preparation for preparing chemical compound 1.With the method preparation that is similar to chemical compound 1 and 2, only in step 2, the indole nitrogen atom is with isopropyl bromide rather than uses the iodomethane alkylation chemical compound 4 and 5 respectively.

Embodiment 8

The chemical compound of general formula shown in above the tool only replaces amine B with amine C with being similar to the method preparation of describing among the embodiment 7.These changes in the method for embodiment 7 are easy to be understood by those of skill in the art in this area.For example, chemical compound 52 and 53 with the method preparation that is similar to chemical compound 2 and 1, only replaces amine B with amine C respectively.

Embodiment 9

The chemical compound of general formula shown in above the tool only replaces amine B with amine A with being similar to the method preparation of describing among the embodiment 7.These changes in the method for embodiment 7 are easy to be understood by those of skill in the art in this area.For example, chemical compound 44 and 45 prepares with the mode that is similar to chemical compound 1 and 2 respectively, only replaces amine B with amine A.

Those of skill in the art can understand and are similar to the reaction of describing in the top scheme and can be used to prepare other formula I chemical compound in this area.Initiation material in the top method is maybe can the preparing by known procedure in this area of obtaining of buying as known in the art.

Chemical compound of the present invention shows antiinflammatory and/or immunoregulatory activity, can be effective to treat various medical conditions, comprise as, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, glaucoma, diabetes, osteoporosis, renal ischaemia, apoplexy, cerebral ischemia, nephritis, psoriasis, allergy, lung and inflammatory diseases of gastro-intestinal tract such as Crohn disease and respiratory tract disease such as reversibility airway obstruction, asthma, chronic obstructive pulmonary disease (COPD) and bronchitis.Effect is proved by following activity analysis.

With with [ ³H] CP-55, the ability of 940 competitions is screened potent cannabinoid receptor ligand, [ ³H] CP-55,940 is known receptors ligand, can combine with the reorganization Cannabined receptor.With test compound from the mother solution of 100%DMSO at dilution buffer liquid (50mM Tris pH7.1,1mM EDTA, 3mM MgCl ₂, 0.1%BSA, 10%DMSO, 0.36% methylcellulose (Sigma M-6385)) and middle serial dilution.(10 μ L) transfers on the 96 hole micro plates with aliquot.With recombined human cannabinoid CB ₂Receptor (Receptor Biology#RB-HCB2) or recombined human cannabinoid CB ₁Receptor (Receptor Biology#RB-HCB ₁) membrane product (3mM MgCI2 is diluted to 0.3mg/mL in 0.1%BSA) for 50mM Tris pH7.2,1mM EDTA at binding buffer liquid.(50 μ L) joins in each hole of micro plate with aliquot.In each hole of micro plate, add [ ³H] CP-55,940 (New England Nuclear#NET1051; Specific activity=180 Ci/mmol) beginning association reaction.Per 100 μ l reactant mixtures comprise 0.48 nM[ ³H] CP-55, the memebrane protein of 940,15 μ g in the binding buffer liquid that comprises 1%DMSO and 0.036% methylcellulose.After at room temperature hatching 2 hours, TomTec Mark 3U catcher (Hamden, GF/C filter plate CT) (UniFilter-96, Packard) filtering reaction thing be housed by what scribble 0.5% polymine coating.With binding buffer liquid washing filter plate 5 times, Rotate 180 °, and then wash 5 times with binding buffer liquid.In PackardTopCount NXT microtest plate scintillation counter, add 30 μ l Packard Microscint20 scintillators and come quantitative binding radioactivity.Prism2.0b is adopted in the nonlinear regression analysis of gained data, and (GraphPad, San Diego CA) carries out.

Find The compounds of this invention show can by Ki value (representing) with nM measure to CB ₂The powerful affinity of receptor.The activity of The compounds of this invention (usefulness) is determined by the Ki value of measuring them.The Ki value is more little, and chemical compound is regulated CB ₂The activity of receptor is big more.The compounds of this invention shows activity in a big way.The CB of the chemical compound of tool formula I ₂Average Ki value is generally＞0nM (as, 0.01nM)-Yue 1000nM, the about 1000nM of preferably about 0.1nM-, the about 100nM of 0.1nM-more preferably from about, even the about 20nM of 0.1nM-more preferably from about.Most preferred for having to CB ₂The average Ki value of receptor is less than the chemical compound of about 20nM.

Find that chemical compound of the present invention shows CB at 0.1-1000nM ₂Receptor-binding activity.For example, chemical compound 20,41,9,13,22,11,6,60,61,31,47,59,62 and 58 Ki value are respectively 0.24,0.4,0.65,1,1,1.46,1.5,3.3,3.9,5,7,25.9,28 and 41nM.

With adjusting CB ₁Receptor is compared, and chemical compound of the present invention also has high selectivity to regulating receptor." selective modulator " is meant the CB of chemical compound ₁The Ki of receptor and CB ₂The optional ratio of the Ki of receptor is greater than about 1, be preferably greater than about 100, more preferably greater than about 500, even more preferably greater than about 1000, most preferably greater than about 3000.For example, chemical compound 20,41,9,13,22,11,6,60,61,31,47,59,62 and 58 CB ₁The Ki of receptor and CB ₂The optional ratio of the Ki of receptor is respectively about 15000,3500,2700,3400,400,1000,6300,4100,1200,71,790,52,1.9 and 770.

Claims

1. the pharmaceutically acceptable salt of the chemical compound of a formula I or described chemical compound or solvate:

Wherein:

B is selected from formula B1-B7:

Or

Each Y independently is selected from-(C (R ⁷) ₂) _p-,-O-(C (R ⁷) ₂) _q-,-(C (R ⁷) ₂) _q-O-,-S-(C (R ⁷) ₂) _r-,-(C (R ⁷) ₂) _r-S-,-S (O)-(C (R ⁷) ₂) _r-,-(C (R ⁷) ₂) _rS (O)-,-S (O ₂)-(C (R ⁷) ₂) _r-,-(C (R ⁷) ₂) _r-S (O ₂)-,-N (R ⁷)-(C (R ⁷) ₂) _r-and-(C (R ⁷) ₂) _rN (R ⁷)-;

Each Z independently is selected from-(C (R ⁷) ₂) _p-,-O-(C (R ⁷) ₂) _q-,-(C (R ⁷) ₂) _q-O-,-S-(C (R ⁷) ₂) _r-,-(C (R ⁷) ₂) _r-S-,-S (O)-(C (R ⁷) ₂) _r-,-(C (R ⁷) ₂) _r-S (O)-,-S (O ₂)-(C (R ⁷) ₂) _r-,-(C (R ⁷) ₂) _r-S (O ₂)-,-N (R ⁷)-(C (R ⁷) ₂) _r-and-(C (R ⁷) ₂) _rN (R ⁷)-;

P is the integer of 1-3;

Q is 1 or 2;

R is the integer of 0-2;

S is 0 or 1, and wherein when s was 0, Z was a covalent bond, and B has two ring structures;

L ¹Be selected from covalent bond ,-(C (R ⁷) ₂) _P-,-C (O)-,-C (O) O-,-OC (O)-,-CH (OR ⁷)-,-S (O ₂)-,-S (O)-,-S-,-O-,-N (R ⁷)-,-C (O) N (R ⁷)-,-N (R ⁷) C (O)-,-OC (O) N (R ⁷)-,-N (R ⁷) C (O) O-,-N (R ⁷) C (O) N (R ⁷)-,-CF ₂-and-C (=N-OR ⁷)-;

L ³Be selected from covalent bond ,-C (R ⁷) ₂-,-C (O)-,-C (O) O-,-OC (O)-,-CH (OR ⁷)-,-S (O ₂) ,-S (O)-,-S-,-O-,-N (R ⁷)-,-C (O) N (R ⁷)-, N (R ⁷) C (O)-,-CF ₂-and-C (=N-OR ⁷)-;

R ¹Be selected from H, alkyl ,-CF ₃,-Si (alkyl) _t(aryl) _3-t, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl,

T is the integer of 0-3;

N is the integer of 0-4;

R ³And R ⁴Identical or different, and be H or alkyl independently,

R ⁵And R ⁶Identical or different, independently be selected from separately H, alkyl, haloalkyl ,-CF ₃, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl,

Wherein each described alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl can be and unsubstitutedly or independent replaced by one or more substituent groups that independently are selected from following groups that can be identical or different: halogen ,-OH, alkoxyl, halogenated alkoxy, alkyl, haloalkyl, alkoxyl, cycloalkyl, cycloalkyl oxy, Heterocyclylalkyl, Heterocyclylalkyl oxygen base, aryl, aryloxy, heteroaryl, heteroaryl oxygen base ,-N (R ⁷) ₂,-C (O) R ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) N (R ⁷) ₂,-N (RR ⁷) C (O) R ⁷,-N (R ⁷) C (O) OR ⁷,-N (R ⁷) C (O) N (R ⁷) ₂,-NO ₂,-CN ,-S (O ₂) R ⁷,-S (O ₂) N (R ⁷) ₂With-N (R ⁷) C (=N-CN) NHR ⁷Or

-N (R ⁵)-L ³-R ⁶Can choose the formation ring system wantonly; With

M is the integer of 0-4.

2. the chemical compound of claim 1, wherein B is one of formula B1-B3.

3. the chemical compound of claim 1, wherein B is one of formula B4-B7.

4. the chemical compound of claim 1, wherein:

L ¹For-C (R ⁷) ₂,-C (O)-,-S (O)-,-C (O) O-,-OC (O)-or-S (O ₂)-;

L ²For-C (R ⁷) ₂-,-C (O)-,-S (O)-or-S (O ₂)-;

L ³For-C (R ⁷) ₂-,-C (O)-,-C (O) O-,-OC (O)-or-S (O ₂)-;

R ¹Be selected from alkyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl,

Wherein each described alkyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl can be and unsubstitutedly or independent replaced by one or more substituent groups that independently are selected from following groups that can be identical or different: halogen, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-N (R ⁷) ₂,-CN, (C ₁-C ₆) alkoxyl and-OH;

R ²For H ,-OH, halogen ,-N (R ⁷) ₂, CF ₃, alkoxyl, alkyl, (C ₁-C ₆) haloalkyl, (C ₃-C ₅) cycloalkyl or-CH ₂-(C ₃-C ₅) cycloalkyl;

R ³And R ⁴Identical or different, and be H or (C independently ₁-C ₆) alkyl;

R ⁵Be H or (C ₁-C ₆) alkyl;

R ⁶Be H, (C ₁-C ₆) alkyl, (C ₃-C ₅) cycloalkyl or haloalkyl; With

X independently is selected from H, halogen, alkyl, haloalkyl, (C ₃-C ₅) cycloalkyl ,-OH, alkoxyl, halogenated alkoxy and-CN.

5. the chemical compound of claim 1, wherein A is represented by formula A1:

6. the chemical compound of claim 1, wherein A is represented by formula A2:

7. the chemical compound of claim 1, wherein A is represented by formula A3:

8. the chemical compound of claim 1, wherein A is represented by formula A4:

9. the chemical compound of claim 1, wherein A is represented by formula A5:

10. the chemical compound of claim 1, wherein B is represented by following formula B1:

Wherein Y is-(C (R ⁷) ₂) _p-, p is the integer of 1-3.

11. the chemical compound of claim 10, wherein p=1.

12. the chemical compound of claim 1, wherein B is represented by following structure:

13. the chemical compound of claim 1, wherein B is represented by following formula B5:

Wherein Z is-(C (R ⁷) ₂) _p-, s=1, p are 1 or 2.

14. the chemical compound of claim 13, wherein B is represented by following structure:

15. the chemical compound of claim 1, wherein A is represented by one of following formula A1-A5:

And B is represented by one of formula B1-B3.

16. the chemical compound of claim 1, wherein A is represented by one of following formula A1-A5:

And B is represented by one of formula B4-B7.

17. the chemical compound of claim 1, wherein L ¹, L ²And L ³Independently be-S (O ₂)-,-C (O) O-,-OC (O)-or-CH ₂-.

18. the chemical compound of claim 1, wherein L ¹, L ²And L ³Respectively do for oneself-S (O ₂)-.

19. the chemical compound of claim 1, wherein R ¹Be selected from fluorophenyl, pyridine radicals, Trifluoromethoxyphen-l and methoxyphenyl.

20. the chemical compound of claim 1, wherein R ⁶Be selected from-CH ₃,-CF ₃And cyclopropyl.

21. the chemical compound of claim 1 is represented by one of following formula M-XIX:

Or

Wherein X be selected from H, F, Cl, Br ,-CH ₃,-CF ₃,-OCH ₃,-OCF ₃,-OH and-CN;

R ²Be selected from H and ethyl; With

R ⁶Be selected from methyl, trifluoromethyl and cyclopropyl.

22. the chemical compound of claim 1 is represented by one of following formula:

Or

R ²Be selected from H and ethyl; With

R ⁶Be selected from methyl, trifluoromethyl and cyclopropyl.

23. the chemical compound of claim 1 is represented by one of following formula:

Or

R ²Be selected from H and ethyl; With

R ⁶Be selected from methyl, trifluoromethyl and cyclopropyl.

24. the chemical compound of claim 1 is represented by one of following formula:

Or

R ²Be selected from H and ethyl; With

R ⁶Be selected from methyl, trifluoromethyl and cyclopropyl.

25. the chemical compound of claim 1, wherein R ⁵Be H, n=1, m=1, L ²For-S (O ₂)-and L ¹, L ³, R ¹, R ⁶,-A-X ,-B-N (R ⁵)-and X such as following table in listed:

26. the chemical compound of claim 1, wherein R ⁵Be H, n=1, m=1, L ²For-S (O ₂)-, and L ¹, L ³, R ¹, R ⁶,-A-X ,-B-N (R ⁵)-listed with X such as following table:

27. the compound or its salt and/or the solvate of structure below the tool:

28. the compound or its salt and/or the solvate of structure below the tool:

29. the compound or its salt and/or the solvate of structure below the tool:

30. the compound or its salt and/or the solvate of structure below the tool:

31. chemical compound or its stereoisomer, salt and/or the solvate of structure below the tool:

32. a Pharmaceutical composition, described compositions comprise chemical compound and one or more pharmaceutical acceptable carriers of one or more claim 1.

33. a method for preparing the Pharmaceutical composition of claim 32, described method comprises: one or more formulas I chemical compound is mixed with one or more pharmaceutical acceptable carriers.

34. regulate patient's cannabinoid CB for one kind ₂The method of receptor, described method comprise having at least a CB ₂The patient CB of receptor ₂The chemical compound of one or more claim 1 of receptor regulated quantity.

35. a method for the treatment of cancer, inflammatory diseases, immunomodulating disease or respiratory system disease, described method comprises: the chemical compound that needs one or more claim 1 of patient of this treatment.

36. the method for claim 35, wherein the amount of one or more formulas I chemical compound is the treatment effective dose.

37. the method for claim 35, wherein said cancer, inflammatory diseases, immunomodulating disease or respiratory system disease are selected from following disease for one or more: cutaneous T cell lymphoma, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, glaucoma, diabetes, sepsis, shock, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal diseases, scleroderma, osteoporosis, renal ischaemia, myocardial infarction, apoplexy, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, CFA, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, the pollinosis, Crohn disease, inflammatory bowel, the reversibility airway obstruction, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD) and bronchitis.

38. the method for claim 37, also comprise can be identical or different with chemical compound and one or more of formula I second medicine altogether administration or administering drug combinations, described second medicine independently be selected from DMARDS, NSAIDS, cox 2 inhibitor, COX-1 inhibitor, immunosuppressant, BRMs, IL-1 antagonist, anti-CD 40 molecule, anti--the CD28 molecule, resist-adhesion molecule and other anti-inflammatory drug.

39. the method for claim 38, wherein said second medicine comprise that one or more independently are selected from the DMARDS of methotrexate, azathioprine, leflunomide, penicillamine, golden salt, mycophenolate and cyclophosphamide.

40. the method for claim 38, wherein said second medicine comprises that one or more independently are selected from the NSAIDS of piroxicam, naproxen, indomethacin and ibuprofen.

41. the method for claim 38, wherein said second medicine comprises piroxicam.

42. the method for claim 38, wherein said second medicine comprises that one or more independently are selected from the cox 2 inhibitor of rofecoxib and celecoxib.

43. the method for claim 38, wherein said second medicine comprises that one or more are selected from the immunosuppressant of steroid, ciclosporin, tacrolimus and rapamycin.

44. the method for claim 38, wherein said second medicine comprise that one or more independently are selected from the BRMs of Embrel, English husband monoclonal antibody, IL-1 antagonist, anti-CD 40, anti--CD28, IL-10 and anti--adhesion molecule.

45. the method for claim 38, wherein said second medicine comprise that one or more are selected from other anti-inflammatory drug of p38 inhibitors of kinases, PDE4 inhibitor, tace inhibitor, chemokine receptor anagonists and Thalidomide.

46. the method for claim 38, wherein said administration are oral or subcutaneous administration.

47. the chemical compound of the claim 1 of a purified form.